U.S. patent application number 10/794099 was filed with the patent office on 2004-09-09 for 1-amino 1h-imidazoquinolines.
This patent application is currently assigned to 3M Innovative Properties Company. Invention is credited to Griesgraber, George W., Manske, Karl J..
Application Number | 20040176367 10/794099 |
Document ID | / |
Family ID | 32994478 |
Filed Date | 2004-09-09 |
United States Patent
Application |
20040176367 |
Kind Code |
A1 |
Griesgraber, George W. ; et
al. |
September 9, 2004 |
1-Amino 1H-imidazoquinolines
Abstract
1-Amino 1H-imidazoquinoline compounds, pharmaceutical
compositions containing the compounds, intermediates, and methods
of making and methods of use of these compounds as
immunomodulators, for modulating cytokine biosynthesis in animals
and in the treatment of diseases including viral and neoplastic
diseases are disclosed.
Inventors: |
Griesgraber, George W.;
(Eagan, MN) ; Manske, Karl J.; (Minneapolis,
MN) |
Correspondence
Address: |
3M INNOVATIVE PROPERTIES COMPANY
PO BOX 33427
ST. PAUL
MN
55133-3427
US
|
Assignee: |
3M Innovative Properties
Company
|
Family ID: |
32994478 |
Appl. No.: |
10/794099 |
Filed: |
March 5, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60453128 |
Mar 7, 2003 |
|
|
|
60532191 |
Dec 23, 2003 |
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Current U.S.
Class: |
514/227.8 ;
514/234.2; 514/253.03; 514/291; 544/361; 544/60; 546/82 |
Current CPC
Class: |
A61P 35/00 20180101;
A61P 37/02 20180101; C07D 471/02 20130101; A61P 31/12 20180101;
A61P 43/00 20180101 |
Class at
Publication: |
514/227.8 ;
514/234.2; 514/253.03; 514/291; 544/060; 544/361; 546/082 |
International
Class: |
A61K 031/541; A61K
031/5377; A61K 031/496; A61K 031/4745; C07D 471/02 |
Claims
What is claimed is:
1. A compound of the Formula (I): 88wherein: R.sub.1' is selected
from the group consisting of hydrogen and alkyl; R.sub.1 is
selected from the group consisting of: --R.sub.4, --Y--R.sub.4,
--X--R.sub.5, --X--N(R.sub.6)--Y--R.sub.4,
--X--C(R.sub.7)--N(R.sub.6)--R.sub.4, and --X--O--R.sub.4; or
R.sub.1' and R.sub.1 together with the nitrogen atom to which they
are bonded can join to form a group selected from the group
consisting of: 89R.sub.4 is selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and
heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl,
and heterocyclyl groups can be unsubstituted or substituted by one
or more substituents independently selected from the group
consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro,
hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy,
arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy,
heterocyclyl, heterocyclylalkylenyl, amino, alkylamino,
(arylalkylenyl)amino, dialkylamino, and in the case of alkyl,
alkenyl, alkynyl, and heterocyclyl, oxo, with the proviso that when
R.sub.4 is a substituted alkyl group and the substituent contains a
hetero atom which bonds directly to the alkyl group then the alkyl
group contains at least two carbons between the substituent and the
nitrogen atom to which R.sub.1 is bonded; R.sub.5 is selected from
the group consisting of: 90each R.sub.6 is independently selected
from the group consisting of hydrogen, alkyl, and arylalkylenyl;
R.sub.7 is selected from the group consisting of .dbd.O and .dbd.S;
R.sub.8 is C.sub.2-7 alkylene; A is selected from the group
consisting of --CH(R.sub.6)--, --O--, --N(R.sub.6)--,
--N(Y--R.sub.4)--, and --N(X--N(R.sub.6)--Y--R.sub.4)--; X is
C.sub.2-20 alkylene; Y is selected from the group consisting of
--C(R.sub.7)--, --C(R.sub.7)--O--, --S(O).sub.2--,
--S(O).sub.2--N(R.sub.6)--, and --C(R.sub.7)--N(R.sub.9)--; wherein
R.sub.9 is selected from the group consisting of hydrogen, alkyl,
and arylalkylenyl; or R.sub.9 and R.sub.4 together with the
nitrogen atom to which R.sub.9 is bonded can join to form the group
91a and b are independently integers from 1 to 4 with the proviso
that when A is --O--, --N(R.sub.6)--, --N(Y--R.sub.4)--, or
--N(X--N(R.sub.6)--Y--R.sub.4)-- then a and b are independently
integers from 2 to 4; each R" is independently hydrogen or a
non-interfering substituent; each R'" is independently a
non-interfering substituent; and n is an integer from 0 to 4; or a
pharmaceutically acceptable salt thereof.
2. The compound or salt of claim 1 wherein the compound induces the
biosynthesis of one or more cytokines.
3. The compound or salt of claim 1 wherein R" is selected from the
group consisting of: -hydrogen, -alkyl, -alkenyl, -aryl,
-heteroaryl, -heterocyclyl, -alkylene-Z-alkyl, -alkylene-Z-aryl,
-alkylene-Z-alkenyl, and -alkyl or alkenyl substituted by one or
more substituents selected from the group consisting of: --OH,
-halogen, --N(R.sub.6).sub.2, --C(R.sub.7)--N(R.sub.6).sub.2,
--S(O).sub.2--N(R.sub.6).sub.2,
--N(R.sub.6)--C(R.sub.7)--C.sub.1-10 alkyl,
--N(R.sub.6)--S(O).sub.2--C.s- ub.1-10 alkyl, --C(O)--C.sub.1-10
alkyl, --C(O)--O--C.sub.1-10 alkyl, --N.sub.3, -aryl, -heteroaryl,
-heterocyclyl, --C(O)-aryl, and --C(O)-heteroaryl; each R.sub.6 is
independently selected from the group consisting of hydrogen,
alkyl, and arylalkylenyl; each R.sub.7 is independently selected
from the group consisting of .dbd.O and .dbd.S; and Z is selected
from the group consisting of --O-- and --S(O).sub.0-2--.
4. The compound or salt of claim 1 wherein: R'" is R or R.sub.3
when n is 1, R or one R and one R.sub.3 when n is 2, or R when n is
3 to 4; R is selected from the group consisting of alkyl, alkenyl,
alkoxy, halogen, fluoroalkyl, hydroxy, amino, alkylamino, and
dialkylamino; R.sub.3 is selected from the group consisting of:
-Z'-R.sub.4', -Z'-X'--R.sub.4', -Z'-X'--Y'--R.sub.4', and
-Z'-X'--R.sub.5'; Z' is a bond or --O--; X' is selected from the
group consisting of alkylene, alkenylene, alkynylene, arylene,
heteroarylene, and heterocyclylene wherein the alkylene,
alkenylene, and alkynylene groups can be optionally interrupted or
terminated by arylene, heteroarylene, or heterocyclylene and
optionally interrupted by one or more --O-- groups; Y' is selected
from the group consisting of: 92R.sub.4' is selected from the group
consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl,
and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl,
and heterocyclyl groups can be unsubstituted or substituted by one
or more substituents independently selected from the group
consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,
halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,
arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,
heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl,
alkynyl, and heterocyclyl, oxo; R.sub.5' is selected from the group
consisting of: 93each R.sub.7 is independently selected from the
group consisting of .dbd.O and .dbd.S; each R.sub.8 is
independently C.sub.2-7 alkylene; R.sub.10 is C.sub.3-8 alkylene;
each R.sub.11 is independently selected from the group consisting
of hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.1-10
alkoxyC.sub.2-10 alkylenyl, and arylC.sub.1-10 alkylenyl; R.sub.12
is selected from the group consisting of hydrogen and alkyl; A' is
selected from the group consisting of --CH.sub.2--, --O--,
--C(O)--, --S(O).sub.0-2--, and --N(R.sub.4')--; Q is selected from
the group consisting of a bond, --C(R.sub.7)--,
--C(R.sub.7)--C(R.sub.7)--, --S(O).sub.2--,
--C(R.sub.7)--N(R.sub.11)--W-- -, --S(O).sub.2--N(R.sub.11)--,
--C(R.sub.7)--O--, and --C(R.sub.7)--N(OR.sub.12)--; V is selected
from the group consisting of --C(R.sub.7)--, --O--C(R.sub.7)--,
--N(R.sub.11)--C(R.sub.7)--, and --S(O).sub.2--; W is selected from
the group consisting of a bond, --C(O)--, and --S(O).sub.2--; and c
and d are independently integers from 1 to 6 with the proviso that
c+d is .ltoreq.7, and when A' is --O--or --N(R.sub.4')-- then c and
d are independently integers from 2 to 4.
5. A compound of the Formula (II): 94wherein: each R.sub.A is
independently selected from the group consisting of: halogen,
hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, --NH.sub.2,
--NH(alkyl), and --N(alkyl).sub.2; n is an integer from 0 to 4;
R.sub.1' is selected from the group consisting of hydrogen and
alkyl; R.sub.1 is selected from the group consisting of: --R.sub.4,
--Y--R.sub.4, --X--R.sub.5, --X--N(R.sub.6)--Y--R.sub.4,
--X--C(R.sub.7)--N(R.sub.6)--R.sub.4, and --X--O--R.sub.4; or
R.sub.1' and R.sub.1 together with the nitrogen atom to which they
are bonded can join to form a group selected from the group
consisting of: 95R.sub.4 is selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and
heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl,
and heterocyclyl groups can be unsubstituted or substituted by one
or more substituents independently selected from the group
consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro,
hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy,
arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy,
heterocyclyl, heterocyclylalkylenyl, amino, alkylamino,
(arylalkylenyl)amino, dialkylamino, and in the case of alkyl,
alkenyl, alkynyl, and heterocyclyl, oxo, with the proviso that when
R.sub.4 is a substituted alkyl group and the substituent contains a
hetero atom which bonds directly to the alkyl group then the alkyl
group contains at least two carbons between the substituent and the
nitrogen atom to which R.sub.1 is bonded; R.sub.5 is selected from
the group consisting of: 96each R.sub.6 is independently selected
from the group consisting of hydrogen, alkyl, and arylalkylenyl;
R.sub.7 is selected from the group consisting of .dbd.O and .dbd.S;
R.sub.8 is C.sub.2-7 alkylene; A is selected from the group
consisting of --CH(R.sub.6)--, --O--, --N(R.sub.6)--,
--N(Y--R.sub.4)--, and --N(X--N(R.sub.6)--Y--R.sub.4)--; X is
C.sub.2-20 alkylene; Y is selected from the group consisting of
--C(R.sub.7)--, --C(R.sub.7)--O--, --S(O).sub.2--,
--S(O).sub.2--N(R.sub.6)--, and --C(R.sub.7)--N(R.sub.9)--; wherein
R.sub.9 is selected from the group consisting of hydrogen, alkyl,
and arylalkylenyl; or R.sub.9 and R.sub.4 together with the
nitrogen atom to which R.sub.9 is bonded can join to form the group
97a and b are independently integers from 1 to 4 with the proviso
that when A is --O--, --N(R.sub.6)--, --N(Y--R.sub.4)--, or
--N(X--N(R.sub.6)--Y--R.sub.4)-- then a and b are independently
integers from 2 to 4; and R" is hydrogen or a non-interfering
substituent; or a pharmaceutically acceptable salt thereof.
6. The compound or salt of claim 5 wherein the compound or salt
induces the biosynthesis of one or more cytokines.
7. A compound of the Formula (I-1): 98wherein: R.sub.1' is selected
from the group consisting of hydrogen and alkyl; R.sub.1 is
selected from the group consisting of: --R.sub.4, --Y--R.sub.4,
--X--R.sub.5, --X--N(R.sub.6)--Y--R.sub.4,
--X--C(R.sub.7)--N(R.sub.6)--R.sub.4, and --X--O--R.sub.4; or
R.sub.1' and R.sub.1 together with the nitrogen atom to which they
are bonded can join to form a group selected from the group
consisting of: 99R.sub.2 is selected from the group consisting of:
-hydrogen, -alkyl, -alkenyl, -aryl, -heteroaryl, -heterocyclyl,
-alkylene-Z-alkyl, -alkylene-Z-aryl, -alkylene-Z-alkenyl, and
-alkyl or alkenyl substituted by one or more substituents selected
from the group consisting of: --OH, -halogen, --N(R.sub.6).sub.2,
--C(R.sub.7)--N(R.sub.6).sub.2, --S(O).sub.2--N(R.sub.6).sub.2,
--N(R)--C(R.sub.7)--C.sub.1-10 alkyl,
--N(R.sub.6)--S(O).sub.2--C.sub.1-1- 0 alkyl, --C(O)--C.sub.1-10
alkyl, --C(O)--O--C.sub.1-10 alkyl, --N.sub.3, -aryl, -heteroaryl,
-heterocyclyl, --C(O)-aryl, and --C(O)-heteroaryl; R.sub.3 is
selected from the group consisting of: -Z'-R.sub.4',
-Z'-X'--R.sub.4', -Z'-X'--Y'--R.sub.4', and -Z'-X'--R.sub.5'; each
R is independently selected from the group consisting of alkyl,
alkenyl, alkoxy, halogen, fluoroalkyl, hydroxy, amino, alkylamino,
and dialkylamino; n is an integer from 0 to 4; m is 0 or 1; with
the proviso that when m is 1, then n is 0 or 1; R.sub.4 is selected
from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,
aryl, heteroaryl, and heterocyclyl wherein the alkyl, alkenyl,
alkynyl, aryl, heteroaryl, and heterocyclyl groups can be
unsubstituted or substituted by one or more substituents
independently selected from the group consisting of alkyl, alkoxy,
haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano,
carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl,
heteroaryloxy, heteroarylalkoxy, heterocyclyl,
heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino,
dialkylamino, and in the case of alkyl, alkenyl, alkynyl, and
heterocyclyl, oxo, with the proviso that when R.sub.4 is a
substituted alkyl group and the substituent contains a hetero atom
which bonds directly to the alkyl group then the alkyl group
contains at least two carbons between the substituent and the
nitrogen atom to which R.sub.1 is bonded; R.sub.5 is selected from
the group consisting of: 100X is C.sub.2-20 alkylene; Y is selected
from the group consisting of --C(R.sub.7)--, --C(R.sub.7)--O--,
--S(O).sub.2--, --S(O).sub.2--N(R.sub.6)--, and
--C(R.sub.7)--N(R.sub.9)--; wherein R.sub.9 is selected from the
group consisting of hydrogen, alkyl, and arylalkylenyl; or R.sub.9
and R.sub.4 together with the nitrogen atom to which R.sub.9 is
bonded can join to form the group 101Z is selected from the group
consisting of --O-- and --S(O).sub.0-2--; A is selected from the
group consisting of --CH(R.sub.6)--, --O--, --N(R.sub.6)--,
--N(Y--R.sub.4)--, and --N(X--N(R.sub.6)--Y--R.sub.4)--; a and b
are independently integers from 1 to 4 with the proviso that when A
is --O--, --N(R.sub.6)--, --N(Y--R.sub.4)--, or
--N(X--N(R.sub.6)--Y--R.sub.4)-- then a and b are independently
integers from 2 to 4; R.sub.4' is selected from the group
consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl,
and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl,
arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl,
heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl,
and heterocyclyl groups can be unsubstituted or substituted by one
or more substituents independently selected from the group
consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,
halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,
arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,
heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl,
alkynyl, and heterocyclyl, oxo; R.sub.5' is selected from the group
consisting of: 102X' is selected from the group consisting of
alkylene, alkenylene, alkynylene, arylene, heteroarylene, and
heterocyclylene wherein the alkylene, alkenylene, and alkynylene
groups can be optionally interrupted or terminated by arylene,
heteroarylene, or heterocyclylene and optionally interrupted by one
or more --O-- groups; Y' is selected from the group consisting of:
103Z' is a bond or --O--; A' is selected from the group consisting
of --CH.sub.2--, --O--, --C(O)--, --S(O).sub.0-2--, and
--N(R.sub.4')--; Q is selected from the group consisting of a bond,
--C(R.sub.7)--, --C(R.sub.7)--C(R.sub.7)--, --S(O).sub.2--,
--C(R.sub.7)--N(R.sub.11)--W--, --S(O).sub.2--N(R.sub.11)--,
--C(R.sub.7)--O--, and --C(R.sub.7)--N(OR.sub.12)--; V is selected
from the group consisting of --C(R.sub.7)--, --O--C(R.sub.7)--,
--N(R.sub.11)--C(R.sub.7)--, and --S(O).sub.2--; W is selected from
the group consisting of a bond, --C(O)--, and --S(O).sub.2--; c and
d are independently integers from 1 to 6 with the proviso that c+d
is .ltoreq.7, and when A' is --O-- or --N(R.sub.4')-- then c and d
are independently integers from 2 to 4; each R.sub.6 is
independently selected from the group consisting of hydrogen,
alkyl, and arylalkylenyl; each R.sub.7 is independently selected
from the group consisting of .dbd.O and .dbd.S; each R.sub.8 is
independently C.sub.2-7 alkylene; R.sub.10 is C.sub.3-8 alkylene;
each R.sub.11 is independently selected from the group consisting
of hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.1-10
alkoxyC.sub.2-10 alkylenyl, and arylC.sub.1-10 alkylenyl; and
R.sub.12 is selected from the group consisting of hydrogen and
alkyl; or a pharmaceutically acceptable salt thereof.
8. The compound or salt according to claim 7 wherein R.sub.1 is
selected from the group consisting of --R.sub.4, --Y--R.sub.4, and
--X--N(R.sub.6)--Y--R.sub.4 wherein Y is --C(R.sub.7)--,
--S(O).sub.2--, or --C(R.sub.7)--N(R.sub.9)--.
9. The compound or salt according to claim 8 wherein R.sub.1 is
selected from the group consisting of hydrogen, alkyl, alkenyl,
arylalkylenyl, arylaikenylenyl, heteroarylalkylenyl,
heteroarylalkenylenyl, aminoalkylenyl, alkoxyalkylenyl, acyl,
alkylsulfonylaminoalkylenyl, arylsulfonylaminoalkylenyl,
alkylaminocarbonyl, arylaminocarbonyl,
(arylalkylenyl)aminoalkylenyl, heterocyclylcarbonylaminoalkylenyl,
and arylaminocarbonylaminoalkylenyl.
10. The compound or salt according to claim 9 wherein R.sub.1 is
selected from the group consisting of hydrogen, methyl, isopropyl,
butyl, 2-methylpropyl, 1-ethylpropyl, 3-methylbutyl, cyclohexyl,
benzyl, 3-phenylpropyl, cinnamyl, furan-2-ylmethyl, and
--CH.sub.2CH.sub.2CH.sub.- 2--NHR.sub.13, wherein R.sub.13 is
selected from the group consisting of methanesulfonyl,
phenylsulfonyl, benzyl, isopropylaminocarbonyl,
morpholine-4-carbonyl, and phenylaminocarbonyl.
11. The compound or salt according to claim 7 wherein R.sub.1' is
hydrogen.
12. The compound or salt of claim 7 wherein R.sub.1 and R.sub.1'
are each independently alkyl.
13. The compound or salt of claim 7 wherein R.sub.1 and R.sub.1'
join to form the group: 104
14. The compound or salt according to claim 7 wherein R.sub.2 is
selected from the group consisting of hydrogen, alkyl, and
alkoxyalkylenyl.
15. The compound or salt according to claim 14 wherein R.sub.2 is
selected from the group consisting of hydrogen, methyl, propyl,
butyl, 2-methoxyethyl, and ethoxymethyl.
16. The compound or salt according to claim 7 wherein n is 0.
17. The compound or salt according to claim 7 wherein n is 0, and
R.sub.3 is selected from the group consisting of -Z'-R.sub.4',
-Z'-X'--R.sub.4', and -Z'-X'--Y'--R.sub.4'.
18. The compound or salt according to claim 17 wherein R.sub.3 is
selected from the group consisting of 2-(pyridin-3-yl)ethyl,
pyridinyl, hydroxymethylpyridinyl, ethoxyphenyl,
(morpholine-4-carbonyl)phenyl, 2-(methanesulfonylamino)ethoxy, and
benzyloxy.
19. A compound of the Formula (I-2): 105wherein: R.sub.B is
selected from the group consisting of alkyl, alkoxy, halogen,
hydroxy, and trifluoromethyl; n is an integer from 0 to 4; R.sub.1'
is selected from the group consisting of hydrogen and alkyl;
R.sub.1 is selected from the group consisting of: --R.sub.4,
--Y--R.sub.4, --X--R.sub.5, --X--N(R.sub.6)--Y--R.sub.4,
--X--C(R.sub.7)--N(R.sub.6)--R.sub.4, and --X--O--R.sub.4; or
R.sub.1' and R.sub.1 together with the nitrogen atom to which they
are bonded can join to form a group selected from the group
consisting of: 106R.sub.2 is selected from the group consisting of:
-hydrogen, -alkyl, -alkenyl, -aryl, -heteroaryl, -heterocyclyl,
-alkylene-Z-alkyl, -alkylene-Z-aryl, -alkylene-Z-alkenyl, and
-alkyl or alkenyl substituted by one or more substituents selected
from the group consisting of: --OH, -halogen, --N(R.sub.6).sub.2,
--C(R.sub.7)--N(R.sub.6).sub.2, --S(O).sub.2--N(R).sub.2,
--N(R.sub.6)--C(R.sub.7)--C.sub.1-10 alkyl,
--N(R.sub.6)--S(O).sub.2--C.s- ub.1-10 alkyl, --C(O)--C.sub.1-10
alkyl, --C(O)--O--C.sub.1-10 alkyl, --N.sub.3, -aryl, -heteroaryl,
-heterocyclyl, --C(O)-aryl, and --C(O)-heteroaryl; R.sub.4 is
selected from the group consisting of hydrogen, alkyl, alkenyl,
alkynyl, aryl, heteroaryl, and heterocyclyl wherein the alkyl,
alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl groups can be
unsubstituted or substituted by one or more substituents
independently selected from the group consisting of alkyl, alkoxy,
haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano,
carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl,
heteroaryloxy, heteroarylalkoxy, heterocyclyl,
heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino,
dialkylamino, and in the case of alkyl, alkenyl, alkynyl, and
heterocyclyl, oxo, with the proviso that when R.sub.4 is a
substituted alkyl group and the substituent contains a hetero atom
which bonds directly to the alkyl group then the alkyl group
contains at least two carbons between the substituent and the
nitrogen atom to which R.sub.1 is bonded; R.sub.5 is selected from
the group consisting of: 107each R.sub.6 is independently selected
from the group consisting of hydrogen, alkyl, and arylalkylenyl;
each R.sub.7 is independently selected from the group consisting of
.dbd.O and .dbd.S; R.sub.8 is C.sub.2-7 alkylene; A is selected
from the group consisting of --CH(R.sub.6)--, --O--,
--N(R.sub.6)--, --N(Y--R.sub.4)--, and
--N(X--N(R.sub.6)--Y--R.sub.4)--; X is C.sub.2-20 alkylene; Y is
selected from the group consisting of --C(R.sub.7)--,
--C(R.sub.7)--O--, --S(O).sub.2--, --S(O).sub.2--N(R.sub.6)--, and
--C(R.sub.7)--N(R.sub.9)-- -; wherein R.sub.9 is selected from the
group consisting of hydrogen, alkyl, and arylalkylenyl; or R.sub.9
and R.sub.4 together with the nitrogen atom to which R.sub.9 is
bonded can join to form the group 108Z is selected from the group
consisting of --O-- and --S(O).sub.0-2--; and a and b are
independently integers from 1 to 4 with the proviso that when A is
--O--, --N(R.sub.6)--, --N(Y--R.sub.4)--, or
--N(X--N(R.sub.6)--Y--R- .sub.4)-- then a and b are independently
integers from 2 to 4; or a pharmaceutically acceptable salt
thereof.
20. The compound or salt according to claim 19 wherein R.sub.1 is
selected from the group consisting of --R.sub.4, --Y--R.sub.4, and
--X--N(R.sub.6)--Y--R.sub.4 wherein Y is --C(R.sub.7)--,
--S(O).sub.2--, or --C(R.sub.7)--N(R.sub.9)--.
21. The compound or salt according to claim 20 wherein R.sub.1 is
selected from the group consisting of hydrogen, alkyl, alkenyl,
arylalkylenyl, arylalkenylenyl, heteroarylalkylenyl,
heteroarylalkenylenyl, aminoalkylenyl, alkoxyalkylenyl, acyl,
alkylsulfonylaminoalkylenyl, arylsulfonylaminoalkylenyl,
alkylaminocarbonyl, arylaminocarbonyl,
(arylalkylenyl)aminoalkylenyl, and
arylaminocarbonylaminoalkylenyl.
22. The compound or salt according to claim 21 wherein R.sub.1 is
selected from the group consisting of hydrogen, methyl, isopropyl,
butyl, 2-methylpropyl, 1-ethylpropyl, 3-methylbutyl, cyclohexyl,
benzyl, cinnamyl, furan-2-ylmethyl, and
--CH.sub.2CH.sub.2CH.sub.2--NHR.sub.13, wherein R.sub.13 is
selected from the group consisting of methanesulfonyl,
phenylsulfonyl, benzyl, and phenylaminocarbonyl.
23. The compound or salt according to claim 19 wherein R.sub.1' is
hydrogen.
24. The compound or salt of claim 19 wherein R.sub.1 and R.sub.1'
are each independently alkyl.
25. The compound or salt of claim 19 wherein R.sub.1 and R.sub.1'
join to form the group: 109
26. The compound or salt according to claim 19 wherein R.sub.2 is
selected from the group consisting of hydrogen, alkyl, and
alkoxyalkylenyl.
27. The compound or salt according to claim 26 wherein R.sub.2 is
selected from the group consisting of hydrogen, butyl,
2-methoxyethyl, and ethoxymethyl.
28. The compound or salt according to claim 19 wherein n is 0.
29. The compound or salt according to claim 19 wherein n is 1, and
R is halogen or hydroxy.
30. A compound of the Formula (I-3): 110wherein: R.sub.B is
selected from alkyl, alkoxy, halogen, hydroxy, and trifluoromethyl;
n is an integer from 0 to 4; R.sub.1' is selected from hydrogen and
alkyl; R.sub.1 is selected from: --R.sub.4, --Y--R.sub.4,
--X--R.sub.5, --X--N(R.sub.6)--Y--R.sub.4,
--X--CR.sub.7--N(R.sub.6)--R.sub.4, and --X--O--R.sub.4; or
R.sub.1' and R.sub.1 together with the nitrogen atom to which they
are bonded can join to form a group selected from: 111R.sub.2A is
selected from: -hydrogen, -alkyl, -alkenyl, -aryl, -heteroaryl,
-alkylene-Z-alkyl, -alkylene-Z-aryl, -alkylene-Z-alkenyl, and
-alkyl or alkenyl substituted by one or more substituents selected
from: --OH, -halogen, --N(R.sub.6).sub.2,
--CR.sub.7--N(R.sub.6).sub.2, --SO.sub.2--N(R.sub.6).sub.2,
--N(R.sub.6)--CR.sub.7--C.sub.1-10 alkyl,
--N(R.sub.6)--SO.sub.2--C.sub.1-10 alkyl, --C(O)--C.sub.1-10 alkyl,
--C(O)--O--C.sub.1-10 alkyl, --N.sub.3, -aryl, -heteroaryl,
-heterocyclyl, --C(O)-aryl, and --C(O)-heteroaryl; R.sub.4 is
selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,
and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl,
heteroaryl, and heterocyclyl groups can be unsubstituted or
substituted by one or more substituents independently selected from
alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,
mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy,
heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl,
heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino,
dialkylamino, and in the case of alkyl, alkenyl, alkynyl, and
heterocyclyl, oxo, with the proviso that when R.sub.4 is a
substituted alkyl group and the substituent contains a hetero atom
which bonds directly to the alkyl group then the alkyl group
contains at least two carbons between the substituent and the
nitrogen atom to which R.sub.1 is bonded; R.sub.5 is selected from:
112R.sub.6 is selected from hydrogen, alkyl, and arylalkylenyl;
R.sub.7 is selected from .dbd.O and .dbd.S; R.sub.9 is C.sub.2-7
alkylene; R.sub.9 is selected from hydrogen, alkyl, and
arylalkylenyl, or R.sub.9 and R.sub.4 together with the nitrogen
atom to which R.sub.9 is bonded can join to form the group 113A is
selected from --CHR.sub.6--, --O--, --N(R.sub.6)--,
--N(Y--R.sub.4)--, and --N(X--N(R.sub.6)--Y--R.sub.4)--; X is
C.sub.2-20 alkylene; Y is selected from --CR.sub.7--, --SO.sub.2--,
--SO.sub.2--N(R.sub.6)--, and --CR.sub.7--N(R.sub.9)--; Z is
selected from --O-- and --S(O).sub.0-2--; a and b are independently
integers from 1 to 4 with the proviso that when A is --O--,
--N(R.sub.6)--, --N(Y--R.sub.4)--, or --N(X--N(R.sub.6)--Y--R-
.sub.4)-- then a and b are independently integers from 2 to 4 and
pharmaceutically acceptable salts thereof.
31. The compound or salt according to claim 30 wherein R.sub.1 is
selected from --R.sub.4, --Y--R.sub.4, and
--X--N(R.sub.6)--Y--R.sub.4 wherein Y is --CR.sub.7--,
--SO.sub.2--, or --CR.sub.7--N(R.sub.9)--.
32. The compound or salt according to claim 31 wherein R.sub.1 is
selected from the group consisting of hydrogen, alkyl, alkenyl,
arylalkylenyl, arylalkenylenyl, heteroarylalkylenyl,
heteroarylalkenylenyl, aminoalkylenyl, alkoxyalkylenyl, acyl,
alkylsulfonylaminoalkylenyl, arylsulfonylaminoalkylenyl,
alkylaminocarbonyl, arylaminocarbonyl,
(arylalkylenyl)aminoalkylenyl, and
arylaminocarbonylaminoalkylenyl.
33. The compound or salt according to claim 32 wherein R.sub.1 is
selected from hydrogen, isopropyl, butyl, cyclohexyl, benzyl,
cinnamyl, and --CH.sub.2CH.sub.2CH.sub.2--NHR.sub.13, wherein
R.sub.13 is selected from methanesulfonyl, phenylsulfonyl, benzyl,
and phenylaminocarbonyl.
34. The compound or salt according to claim 30 wherein R.sub.1' is
hydrogen.
35. The compound or salt according to claim 30 wherein R.sub.2A is
selected from hydrogen, alkyl, and alkoxyalkylenyl.
36. The compound or salt according to claim 35 wherein R.sub.2A is
selected from hydrogen, butyl, methoxyethyl, and ethoxymethyl.
37. The compound or salt according to claim 30 wherein n is 0.
38. A compound of the Formula (II-1): 114wherein: each R.sub.A is
independently selected from the group consisting of: halogen,
hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, --NH.sub.2,
--NH(alkyl), and --N(alkyl).sub.2; n is an integer from 0 to 4;
R.sub.1' is selected from the group consisting of hydrogen and
alkyl; R.sub.1 is selected from the group consisting of: --R.sub.4,
--Y--R.sub.4, --X--R.sub.5, --X--N(R.sub.6)--Y--R.sub.4,
--X--C(R.sub.7)--N(R.sub.6)--R.sub.4, and --X--O--R.sub.4; or
R.sub.1' and R.sub.1 together with the nitrogen atom to which they
are bonded can join to form a group selected from the group
consisting of: 115R.sub.2 is selected from the group consisting of:
-hydrogen, -alkyl, -alkenyl, -aryl, -heteroaryl, -heterocyclyl,
-alkylene-Z-alkyl, -alkylene-Z-aryl, -alkylene-Z-alkenyl, and
-alkyl or alkenyl substituted by one or more substituents selected
from the group consisting of: --OH, -halogen, --N(R.sub.6).sub.2,
--C(R.sub.7)--N(R.sub.6).sub.2, --S(O).sub.2--N(R.sub.6).sub.2,
--N(R.sub.6)--C(R.sub.7)--C.sub.1-10 alkyl,
--N(R.sub.6)--S(O).sub.2--C.s- ub.1-10 alkyl, --C(O)--C.sub.1-10
alkyl, --C(O)--O--C.sub.1-10 alkyl, --N.sub.3, -aryl, -heteroaryl,
-heterocyclyl, --C(O)-aryl, and --C(O)-heteroaryl; R.sub.4 is
selected from the group consisting of hydrogen, alkyl, alkenyl,
alkynyl, aryl, heteroaryl, and heterocyclyl wherein the alkyl,
alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl groups can be
unsubstituted or substituted by one or more substituents
independently selected from the group consisting of alkyl, alkoxy,
haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano,
carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl,
heteroaryloxy, heteroarylalkoxy, heterocyclyl,
heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino,
dialkylamino, and in the case of alkyl, alkenyl, alkynyl, and
heterocyclyl, oxo, with the proviso that when R.sub.4 is a
substituted alkyl group and the substituent contains a hetero atom
which bonds directly to the alkyl group then the alkyl group
contains at least two carbons between the substituent and the
nitrogen atom to which R.sub.1 is bonded; R.sub.5 is selected from
the group consisting of: 116each R.sub.6 is independently selected
from the group consisting of hydrogen, alkyl, and arylalkylenyl;
each R.sub.7 is independently selected from the group consisting of
.dbd.O and .dbd.S; R.sub.8 is C.sub.2-7 alkylene; A is selected
from the group consisting of --CH(R.sub.6)--, --O--,
--N(R.sub.6)--, --N(Y--R.sub.4)--, and
--N(X--N(R.sub.6)--Y--R.sub.4)--; X is C.sub.2-20 alkylene; Y is
selected from the group consisting of --C(R.sub.7)--,
--C(R.sub.7)--O--, --S(O).sub.2--, --S(O).sub.2--N(R.sub.6)--, and
--C(R.sub.7)--N(R.sub.9)-- -; wherein R.sub.9 is selected from the
group consisting of hydrogen, alkyl, and arylalkylenyl; or R.sub.9
and R.sub.4 together with the nitrogen atom to which R.sub.9 is
bonded can join to form the group 117Z is selected from the group
consisting of --O-- and --S(O).sub.0-2--; and a and b are
independently integers from 1 to 4 with the proviso that when A is
--O--, --N(R.sub.6)--, --N(Y--R.sub.4)--, or
--N(X--N(R.sub.6)--Y--R- .sub.4)-- then a and b are independently
integers from 2 to 4; or a pharmaceutically acceptable salt
thereof.
39. The compound or salt according to claim 38 wherein R.sub.1 is
selected from the group consisting of --R.sub.4, --Y--R.sub.4, and
--X--N(R.sub.6)--Y--R.sub.4 wherein Y is --C(R.sub.7)--,
--S(O).sub.2--, or --C(R.sub.7)--N(R.sub.9)--.
40. The compound or salt according to claim 39 wherein R.sub.1 is
selected from the group consisting of hydrogen, alkyl, alkenyl,
arylalkylenyl, arylalkenylenyl, heteroarylalkylenyl,
heteroarylalkenylenyl, aminoalkylenyl, alkoxyalkylenyl, acyl,
alkylsulfonylaminoalkylenyl, arylsulfonylaminoalkylenyl,
alkylaminocarbonyl, arylaminocarbonyl,
(arylalkylenyl)aminoalkylenyl, and
arylaminocarbonylaminoalkylenyl.
41. The compound or salt according to claim 39 wherein R.sub.1 is
selected from the group consisting of hydrogen, alkyl, alkenyl,
arylalkylenyl, arylalkenylenyl, heteroarylalkylenyl,
heteroarylalkenylenyl, aminoalkylenyl, alkoxyalkylenyl, acyl,
alkylsulfonylaminoalkylenyl, arylsulfonylaminoalkylenyl,
alkylaminocarbonyl, arylaminocarbonyl,
(arylalkylenyl)aminoalkylenyl, heterocyclylcarbonylaminoalkylenyl,
and arylaminocarbonylaminoalkylenyl.
42. The compound or salt according to claim 40 wherein R.sub.1 is
selected from the group consisting of hydrogen, methyl, isopropyl,
butyl, 2-methylpropyl, 1-ethylpropyl, 3-methylbutyl, cyclohexyl,
benzyl, cinnamyl, furan-2-ylmethyl, and
--CH.sub.2CH.sub.2CH.sub.2--NHR.sub.13, wherein R.sub.13 is
selected from the group consisting of methanesulfonyl,
phenylsulfonyl, benzyl, and phenylaminocarbonyl.
43. The compound or salt according to claim 41 wherein R.sub.1 is
selected from the group consisting of hydrogen, methyl, isopropyl,
butyl, 2-methylpropyl, 1-ethylpropyl, 3-methylbutyl, cyclohexyl,
benzyl, 3-phenylpropyl, cinnamyl, furan-2-ylmethyl, and
--CH.sub.2CH.sub.2CH.sub.- 2--NHR.sub.13, wherein R.sub.13 is
selected from the group consisting of methanesulfonyl,
phenylsulfonyl, benzyl, isopropylaminocarbonyl,
morpholine-4-carbonyl, and phenylaminocarbonyl.
44. The compound or salt according to claim 38 wherein R.sub.1' is
hydrogen.
45. The compound or salt of claim 38 wherein R.sub.1 and R.sub.1'
are each independently alkyl.
46. The compound or salt of claim 38 wherein R.sub.1 and R.sub.1'
join to form the group: 118
47. The compound or salt according to claim 38 wherein R.sub.2 is
selected from the group consisting of hydrogen, alkyl, and
alkoxyalkylenyl.
48. The compound or salt according to claim 47 wherein R.sub.2 is
selected from the group consisting of hydrogen, butyl,
2-methoxyethyl, and ethoxymethyl.
49. The compound or salt according to claim 47 wherein R.sub.2 is
selected from the group consisting of hydrogen, methyl, propyl,
butyl, 2-methoxyethyl, and ethoxymethyl.
50. The compound or salt according to claim 38 wherein n is 0.
51. A pharmaceutical composition comprising a therapeutically
effective amount of a compound or salt of claim 1 and a
pharmaceutically acceptable carrier.
52. A pharmaceutical composition comprising a therapeutically
effective amount of a compound or salt of claim 5 and a
pharmaceutically acceptable carrier.
53. A pharmaceutical composition comprising a therapeutically
effective amount of a compound or salt of claim 7 and a
pharmaceutically acceptable carrier.
54. A pharmaceutical composition comprising a therapeutically
effective amount of a compound or salt of claim 19 and a
pharmaceutically acceptable carrier.
55. A pharmaceutical composition comprising a therapeutically
effective amount of a compound or salt of claim 30 and a
pharmaceutically acceptable carrier.
56. A pharmaceutical composition comprising a therapeutically
effective amount of a compound or salt of claim 38 and a
pharmaceutically acceptable carrier.
57. A method of inducing cytokine biosynthesis in an animal
comprising administering an effective amount of a compound or salt
of claim 1 to the animal.
58. A method of inducing cytokine biosynthesis in an animal
comprising administering an effective amount of a compound or salt
of claim 5 to the animal.
59. A method of inducing cytokine biosynthesis in an animal
comprising administering an effective amount of a compound or salt
of claim 7 to the animal.
60. A method of inducing cytokine biosynthesis in an animal
comprising administering an effective amount of a compound or salt
of claim 19 to the animal.
61. A method of inducing cytokine biosynthesis in an animal
comprising administering an effective amount of a compound or salt
of claim 30 to the animal.
62. A method of inducing cytokine biosynthesis in an animal
comprising administering an effective amount of a compound or salt
of claim 38 to the animal.
63. A method of treating a viral disease in an animal in need
thereof comprising administering to the animal a therapeutically
effective amount of a compound or salt of claim 1.
64. A method of treating a viral disease in an animal in need
thereof comprising administering to the animal a therapeutically
effective amount of a compound or salt of claim 5.
65. A method of treating a viral disease in an animal in need
thereof comprising administering to the animal a therapeutically
effective amount of a compound or salt of claim 7.
66. A method of treating a viral disease in an animal in need
thereof comprising administering to the animal a therapeutically
effective amount of a compound or salt of claim 19.
67. A method of treating a viral disease in an animal in need
thereof comprising administering to the animal a therapeutically
effective amount of a compound or salt of claim 30.
68. A method of treating a viral disease in an animal in need
thereof comprising administering to the animal a therapeutically
effective amount of a compound or salt of claim 38.
69. A method of treating a neoplastic disease in an animal in need
thereof comprising administering to the animal a therapeutically
effective amount of a compound or salt of claim 1.
70. A method of treating a neoplastic disease in an animal in need
thereof comprising administering to the animal a therapeutically
effective amount of a compound or salt of claim 5.
71. A method of treating a neoplastic disease in an animal in need
thereof comprising administering to the animal a therapeutically
effective amount of a compound or salt of claim 7.
72. A method of treating a neoplastic disease in an animal in need
thereof comprising administering to the animal a therapeutically
effective amount of a compound or salt of claim 19.
73. A method of treating a neoplastic disease in an animal in need
thereof comprising administering to the animal a therapeutically
effective amount of a compound or salt of claim 30.
74. A method of treating a neoplastic disease in an animal in need
thereof comprising administering to the animal a therapeutically
effective amount of a compound or salt of claim 38.
75. A compound of the Formula (VII): 119wherein: each R.sub.B is
independently selected from the group consisting of alkyl, alkoxy,
halogen, hydroxy, and trifluoromethyl; n is an integer from 0 to 4;
R.sub.2 is selected from the group consisting of: -hydrogen,
-alkyl, -alkenyl, -aryl, -heteroaryl, -heterocyclyl,
-alkylene-Z-alkyl, -alkylene-Z-aryl, -alkylene-Z-alkenyl, and
-alkyl or alkenyl substituted by one or more substituents selected
from the group consisting of: --OH, -halogen, --N(R.sub.6).sub.2,
--C(R.sub.7)--N(R.sub.6).sub.2, --S(O).sub.2--N(R.sub.6).sub.2,
--N(R.sub.6)--C(R.sub.7)--C.sub.1-10 alkyl, --N(R.sub.6)--
S(O).sub.2--C.sub.1-10 alkyl, --C(O)--C.sub.1-10 alkyl,
--C(O)--O--C.sub.1-10 alkyl, --N.sub.3, -aryl, -heteroaryl,
-heterocyclyl, --C(O)-aryl, and --C(O)-heteroaryl; each R.sub.6 is
independently selected from the group consisting of hydrogen,
alkyl, and arylalkylenyl; R.sub.7 is selected from the group
consisting of .dbd.O and .dbd.S; and Z is selected from the group
consisting of --O--and --S(O).sub.0-2--; or a pharmaceutically
acceptable salt thereof
76. A compound of the Formula (IX): 120wherein: each R.sub.B is
independently selected from the group consisting of alkyl, alkoxy,
halogen, hydroxy, and trifluoromethyl; n is an integer from 0 to 4;
R.sub.1' is hydrogen or alkyl; R.sub.1 is selected from the group
consisting of: --R.sub.4, --Y--R.sub.4, --X--R.sub.5,
--X--N(R.sub.6)--Y--R.sub.4, --X--C(R.sub.7)--N(R.sub.6)--R.sub.4,
and --X--O--R.sub.4; or R.sub.1' and R.sub.1 together with the
nitrogen atom to which they are bonded can join to form a group
selected from the group consisting of: 121R.sub.2 is selected from
the group consisting of: -hydrogen, -alkyl, -alkenyl, -aryl,
-heteroaryl, -heterocyclyl, -alkylene-Z-alkyl, -alkylene-Z-aryl,
-alkylene-Z-alkenyl, and -alkyl or alkenyl substituted by one or
more substituents selected from the group consisting of: --OH,
-halogen, --N(R.sub.6).sub.2, --C(R.sub.7)--N(R.sub.6).sub.2,
--S(O).sub.2--N(R.sub.6).sub.2,
--N(R.sub.6)--C(R.sub.7)--C.sub.1-10 alkyl,
--N(R.sub.6)--S(O).sub.2--C.s- ub.1-10 alkyl, --C(O)--C.sub.1-10
alkyl, --C(O)--O--C.sub.1-10 alkyl, --N.sub.3, -aryl, -heteroaryl,
-heterocyclyl, --C(O)-aryl, and --C(O)-heteroaryl; R.sub.4 is
selected from the group consisting of hydrogen, alkyl, alkenyl,
alkynyl, aryl, heteroaryl, and heterocyclyl wherein the alkyl,
alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl groups can be
unsubstituted or substituted by one or more substituents
independently selected from the group consisting of alkyl, alkoxy,
haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano,
carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl,
heteroaryloxy, heteroarylalkoxy, heterocyclyl,
heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino,
dialkylamino, and in the case of alkyl, alkenyl, alkynyl, and
heterocyclyl, oxo, with the proviso that when R.sub.4 is a
substituted alkyl group and the substituent contains a hetero atom
which bonds directly to the alkyl group then the alkyl group
contains at least two carbons between the substituent and the
nitrogen atom to which R.sub.1 is bonded; R.sub.5 is selected from
the group consisting of 122each R.sub.6 is independently selected
from the group consisting of hydrogen, alkyl, and arylalkylenyl;
each R.sub.7 is independently selected from the group consisting of
.dbd.O and .dbd.S; R.sub.8 is C.sub.2-7 alkylene; A is selected
from the group consisting of --CH(R.sub.6)--, --O--,
--N(R.sub.6)--, --N(Y--R.sub.4)--, and
--N(X--N(R.sub.6)--Y--R.sub.4)--; X is C.sub.2-20 alkylene; Y is
selected from the group consisting of --C(R.sub.7)--,
--C(R.sub.7)--O--, --S(O).sub.2--, --S(O).sub.2--N(R.sub.6)--, and
--C(R.sub.7)--N(R.sub.9)-- -; wherein R.sub.9 is selected from the
group consisting of hydrogen, alkyl, and arylalkylenyl; or R.sub.9
and R.sub.4 together with the nitrogen atom to which R.sub.9 is
bonded can join to form the group 123Z is selected from the group
consisting of --O-- and --S(O).sub.0-2--; and a and b are
independently integers from 1 to 4 with the proviso that when A is
--O--, --N(R.sub.6)--, --N(Y--R.sub.4)--, or
--N(X--N(R.sub.6)--Y--R- .sub.4)-- then a and b are independently
integers from 2 to 4; or a pharmaceutically acceptable salt
thereof
77. A compound of the Formula (X): 124wherein: each R.sub.B is
independently selected from the group consisting of alkyl, alkoxy,
halogen, hydroxy, and trifluoromethyl; n is an integer from 0 to 4;
R.sub.1' is hydrogen or alkyl; R.sub.1a is selected from the group
consisting of: --R.sub.4a, --Y--R.sub.4a, --X--R.sub.5,
--X--N(R.sub.6)--Y--R.sub.4a,
--X--C(R.sub.7)--N(R.sub.6)--R.sub.4a, and --X--O--R.sub.4a; or
R.sub.1' and R.sub.1a together with the nitrogen atom to which they
are bonded can join to form a group selected from the group
consisting of: 125R.sub.2a is selected from the group consisting
of: -hydrogen, -alkyl, -alkenyl, -aryl, -alkylene-Z"-alkyl,
-alkylene-Z"-aryl, -alkylene-Z"-alkenyl, and -alkyl or alkenyl
substituted by one or more substituents selected from the group
consisting of: --OH, -halogen, --N(R.sub.6).sub.2,
--C(R.sub.7)--N(R.sub.6).sub.2, --S(O).sub.2--N(R.sub.6).sub.2,
--N(R.sub.6)--C(R.sub.7)--C.sub.1-10 alkyl,
--N(R.sub.6)--S(O).sub.2--C.s- ub.1-10 alkyl, --C(O)--C.sub.1-10
alkyl, --C(O)--O--C.sub.1-10 alkyl, --N.sub.3, -aryl,
-heterocyclyl, and --C(O)-aryl; R.sub.4a is selected from the group
consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, and
heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, and
heterocyclyl groups can be unsubstituted or substituted by one or
more substituents independently selected from the group consisting
of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,
cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heterocyclyl,
heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino,
dialkylamino, and in the case of alkyl, alkenyl, alkynyl, and
heterocyclyl, oxo, with the proviso that when R.sub.4a is a
substituted alkyl group and the substituent contains a hetero atom
which bonds directly to the alkyl group then the alkyl group
contains at least two carbons between the substituent and the
nitrogen atom to which R.sub.1 is bonded; R.sub.5 is selected from
the group consisting of 126each R.sub.6 is independently selected
from the group consisting of hydrogen, alkyl, and arylalkylenyl;
each R.sub.7 is independently selected from the group consisting of
.dbd.O and .dbd.S; R.sub.8 is C.sub.2-7 alkylene; A is selected
from the group consisting of --CH(R.sub.6)--, --O--,
--N(R.sub.6)--, --N(Y--R.sub.4)--, and
--N(X--N(R.sub.6)--Y--R.sub.4)--; X is C.sub.2-20 alkylene; Y is
selected from the group consisting of --C(R.sub.7)--,
--C(R.sub.7)--O--, --S(O).sub.2--, --S(O).sub.2--N(R.sub.6)--, and
--C(R.sub.7)--N(R.sub.9)-- -; wherein R.sub.9 is selected from the
group consisting of hydrogen, alkyl and arylalkylenyl, or R.sub.9
and R.sub.4 together with the nitrogen atom to which R.sub.9 is
bonded can join to form the group 127Z" is selected from the group
consisting of --O-- and --S(O).sub.2--; and a and b are
independently integers from 1 to 4 with the proviso that when A is
--O--, --N(R.sub.6)--, --N(Y--R.sub.4)--, or
--N(X--N(R.sub.6)--Y--R.sub.4)-- then a and b are independently
integers from 2 to 4; or a pharmaceutically acceptable salt
thereof.
78. A compound of the Formula (XLII): 128wherein: R is selected
from the group consisting of alkyl, alkenyl, alkoxy, halogen,
fluoroalkyl, hydroxy, amino, alkylamino, and dialkylamino; l is 0
or 1; R.sub.2 is selected from the group consisting of: -hydrogen,
-alkyl, -alkenyl, -aryl, -heteroaryl, -heterocyclyl,
-alkylene-Z-alkyl, -alkylene-Z-aryl, -alkylene-Z-alkenyl, and
-alkyl or alkenyl substituted by one or more substituents selected
from the group consisting of: --OH, -halogen, --N(R.sub.6).sub.2,
--C(R.sub.7)--N(R.sub.6).sub.2, --S(O).sub.2--N(R.sub.6).sub.2,
--N(R.sub.6)--C(R.sub.7)--C.sub.1-10 alkyl,
--N(R.sub.6)--S(O).sub.2--C.sub.1-10 alkyl, --C(O)--C.sub.1-10
alkyl, --C(O)--O--C.sub.1-10 alkyl, --N.sub.3, -aryl, -heteroaryl,
-heterocyclyl, --C(O)-aryl, and --C(O)-heteroaryl; each R.sub.6 is
independently selected from the group consisting of hydrogen,
alkyl, and arylalkylenyl; R.sub.7 is selected from the group
consisting of .dbd.O and .dbd.S; and Z is selected from the group
consisting of --O-- and --S(O).sub.0-2--; or a pharmaceutically
acceptable salt thereof.
79. A compound of the Formula (XLIII): 129wherein: R is selected
from the group consisting of alkyl, alkenyl, alkoxy, halogen,
fluoroalkyl, hydroxy, amino, alkylamino, and dialkylamino; l is 0
or 1; R.sub.1' is hydrogen or alkyl; R.sub.1 is selected from the
group consisting of: --R.sub.4, --Y--R.sub.4, --X--R.sub.5,
--X--N(R.sub.6)--Y--R.sub.4, --X--C(R.sub.7)--N(R.sub.6)--R.sub.4,
and --X--O--R.sub.4; or R.sub.1' and R.sub.1 together with the
nitrogen atom to which they are bonded can join to form a group
selected from the group consisting of: 130R.sub.2 is selected from
the group consisting of: -hydrogen, -alkyl, -alkenyl, -aryl,
-heteroaryl, -heterocyclyl, -alkylene-Z-alkyl, -alkylene-Z-aryl,
-alkylene-Z-alkenyl, and -alkyl or alkenyl substituted by one or
more substituents selected from the group consisting of: --OH,
-halogen, --N(R.sub.6).sub.2, --C(R.sub.7)--N(R.sub.6).sub.2,
--S(O).sub.2--N(R.sub.6).sub.2,
--N(R.sub.6)--C(R.sub.7)--C.sub.1-10 alkyl,
--N(R.sub.6)--S(O).sub.2--C.sub.1-10 alkyl, --C(O)--C.sub.1-10
alkyl, --C(O)--O--C.sub.1-10 alkyl, --N.sub.3, -aryl, -heteroaryl,
-heterocyclyl, --C(O)-aryl, and --C(O)-heteroaryl; R.sub.4 is
selected from the group consisting of hydrogen, alkyl, alkenyl,
alkynyl, aryl, heteroaryl, and heterocyclyl wherein the alkyl,
alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl groups can be
unsubstituted or substituted by one or more substituents
independently selected from the group consisting of alkyl, alkoxy,
haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano,
carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl,
heteroaryloxy, heteroarylalkoxy, heterocyclyl,
heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino,
dialkylamino, and in the case of alkyl, alkenyl, alkynyl, and
heterocyclyl, oxo, with the proviso that when R.sub.4 is a
substituted alkyl group and the substituent contains a hetero atom
which bonds directly to the alkyl group then the alkyl group
contains at least two carbons between the substituent and the
nitrogen atom to which R.sub.1 is bonded; R.sub.5 is selected from
the group consisting of 131each R.sub.6 is independently selected
from the group consisting of hydrogen, alkyl, and arylalkylenyl;
each R.sub.7 is independently selected from the group consisting of
.dbd.O and .dbd.S; R.sub.8 is C.sub.2-7 alkylene; A is selected
from the group consisting of --CH(R.sub.6)--, --O--,
--N(R.sub.6)--, --N(Y--R.sub.4)--, and
--N(X--N(R.sub.6)--Y--R.sub.4)--; X is C.sub.2-20 alkylene; Y is
selected from the group consisting of --C(R.sub.7)--,
--C(R.sub.7)--O--, --S(O).sub.2--, --S(O).sub.2--N(R.sub.6)--, and
--C(R.sub.7)--N(R.sub.9)--; wherein R.sub.9 is selected from the
group consisting of hydrogen, alkyl, and arylalkylenyl; or R.sub.9
and R.sub.4 together with the nitrogen atom to which R.sub.9 is
bonded can join to form the group 132Z is selected from the group
consisting of --O-- and --S(O).sub.0-2--; and a and b are
independently integers from 1 to 4 with the proviso that when A is
--O--, --N(R.sub.6)--, --N(Y--R.sub.4)--, or
--N(X--N(R.sub.6)--Y--R.sub.4)-- then a and b are independently
integers from 2 to 4; or a pharmaceutically acceptable salt
thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims priority to U.S. Provisional
Application No. 60/453,128, filed Mar. 7, 2003, and to U.S.
Provisional Application No. 60/532,191, filed Dec. 23, 2003, which
are both incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
[0002] This invention relates to 1-amino 1H-imidazoquinoline
compounds, pharmaceutical compositions containing such compounds,
intermediates used in their preparation, and the use of these
compounds as immunomodulators.
BACKGROUND OF THE INVENTION
[0003] There has been a major effort in recent years to find
compounds that modulate the immune system. Examples of such
compounds, which have demonstrated cytokine inducing and
immunomodulating activity, are disclosed by U.S. Pat. Nos.
4,689,338; 4,929,624; 5,266,575; 5,268,376; 5,352,784; 5,389,640;
5,446,153; 5,482,936; 5,494,916; 5,756,747; 6,110,929; 6,194,425;
6,331,539; 6,376,669; 6,451,810; 6,525,064; 6,541,485; 6,545,016;
6,545,017; 6,656,938; 6,660,735; 6,660,747; 6,664,260; 6,664,264;
6,664,265; 6,667,312; 6,670,372; 6,677,347; 6,677,348; and
6,683,088.
[0004] But despite important progress in the effort to find
immunomodulating compounds, there is still a critical scientific
and medical need for additional compounds that have an ability to
modulate aspects of the immune response, by induction of cytokine
biosynthesis or other mechanisms.
SUMMARY OF THE INVENTION
[0005] It has now been found that certain 1-amino
1H-imidazoquinoline compounds modulate cytokine biosynthesis. In
one aspect, the present invention provides compounds of the
Formulas I and II: 1
[0006] and more specifically the following compounds of the
Formulas I-1, I-2, I-3, and II-1: 2
[0007] wherein R.sub.1', R.sub.1, R.sub.2, R.sub.2A, R.sub.3, R",
R'", R, R.sub.A, R.sub.B, n and m are as defined below; and
pharmaceutically acceptable salts thereof.
[0008] The compounds of Formulas I, I-1, I-2, I-3, II, and II-1 are
useful as immune response modifiers (IRMs) due to their ability to
modulate cytokine biosynthesis (e.g., induce or inhibit the
biosynthesis or production of one or more cytokines) and otherwise
modulate the immune response when administered to animals.
Compounds can be tested per the test procedures described in the
Examples Section. Compounds can be tested for induction of cytokine
biosynthesis by incubating human PBMC in a culture with the
compound(s) at a concentration range of 30 to 0.014 .mu.M and
analyzing for interferon (.alpha.) or tumor necrosis factor
(.alpha.) in the culture supernatant. Compounds can be tested for
inhibition of cytokine biosynthesis by incubating mouse macrophage
cell line Raw 264.7 in a culture with the compound(s) at a single
concentration of, for example, 5 .mu.M and analyzing for tumor
necrosis factor (.alpha.) in the culture supernatant. The ability
to modulate cytokine biosynthesis, for example, induce the
biosynthesis of one or more cytokines, makes the compounds useful
in the treatment of a variety of conditions such as viral diseases
and neoplastic diseases, that are responsive to such changes in the
immune response.
[0009] In another aspect, the present invention provides
pharmaceutical compositions containing the immune response modifier
compounds, and methods of inducing cytokine biosynthesis in animal
cells, treating a viral disease in an animal, and/or treating a
neoplastic disease in an animal by administering to the animal one
or more compounds of the Formulas I, I-1, I-2, I-3, II, and/or
II-1, and/or pharmaceutically acceptable salts thereof.
[0010] In another aspect, the invention provides methods of
synthesizing the compounds of Formulas I, I-1, I-2, I-3, II, and
II-1 and intermediates useful in the synthesis of these
compounds.
[0011] As used herein, "a," "an," "the," "at least one," and "one
or more" are used interchangeably.
[0012] The terms "comprising" and variations thereof do not have a
limiting meaning where these terms appear in the description and
claims.
[0013] The above summary of the present invention is not intended
to describe each disclosed embodiment or every implementation of
the present invention. The description that follows more
particularly exemplifies illustrative embodiments. Guidance is also
provided herein through lists of examples, which can be used in
various combinations. In each instance, the recited list serves
only as a representative group and should not be interpreted as an
exclusive list.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS OF THE
INVENTION
[0014] In one aspect, the present invention provides 1-amino
1H-imidazoquinoline compounds of the following Formula I: 3
[0015] wherein:
[0016] R.sub.1' is selected from the group consisting of hydrogen
and alkyl;
[0017] R.sub.1 is selected from the group consisting of:
[0018] --R.sub.4,
[0019] --Y--R.sub.4,
[0020] --X--R.sub.5,
[0021] --X--N(R.sub.6)--Y--R.sub.4,
[0022] --X--C(R.sub.7)--N(R.sub.6)--R.sub.4, and
[0023] --X--O--R.sub.4;
[0024] or R.sub.1' and R.sub.1 together with the nitrogen atom to
which they are bonded can join to form a group selected from the
group consisting of: 4
[0025] R.sub.4is selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl wherein
the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl
groups can be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of
alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,
mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy,
heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl,
heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino,
dialkylamino, and in the case of alkyl, alkenyl, alkynyl, and
heterocyclyl, oxo, with the proviso that when R.sub.4is a
substituted alkyl group and the substituent contains a hetero atom
which bonds directly to the alkyl group then the alkyl group
contains at least two carbons between the substituent and the
nitrogen atom to which R.sub.1 is bonded;
[0026] R.sub.5is selected from the group consisting of: 5
[0027] each R.sub.6is independently selected from the group
consisting of hydrogen, alkyl, and arylalkylenyl;
[0028] R.sub.7 is selected from the group consisting of .dbd.O and
.dbd.S;
[0029] R.sub.8 is C.sub.2-7 alkylene;
[0030] A is selected from the group consisting of --CH(R.sub.6)--,
--O--, --N(R.sub.6)--, --N(Y--R.sub.4)--, and
--N(X--N(R.sub.6)--Y--R.sub.4)--;
[0031] X is C.sub.2-20 alkylene;
[0032] Y is selected from the group consisting of --C(R.sub.7)--,
--C(R.sub.7)--O--, --S(O).sub.2--, --S(O).sub.2--N(R.sub.6)--, and
--C(R.sub.7)--N(R.sub.9)--; wherein R.sub.9 is selected from the
group consisting of hydrogen, alkyl, and arylalkylenyl; or R.sub.9
and R.sub.4 together with the nitrogen atom to which R.sub.9 is
bonded can join to form the group 6
[0033] a and b are independently integers from 1 to 4 with the
proviso that when A is --O--, --N(R.sub.6)--, --N(Y--R.sub.4)--, or
--N(X--N(R.sub.6)--Y--R.sub.4)-- then a and b are independently
integers from 2 to 4;
[0034] each R" is independently hydrogen or a non-interfering
substituent;
[0035] each R'" is independently a non-interfering substituent;
and
[0036] n is an integer from 0 to 4;
[0037] or a pharmaceutically acceptable salt thereof.
[0038] In some embodiments of Formula I, R" is selected from the
group consisting of:
[0039] -hydrogen,
[0040] -alkyl,
[0041] -alkenyl,
[0042] -aryl,
[0043] -heteroaryl,
[0044] -heterocyclyl,
[0045] -alkylene-Z-alkyl,
[0046] -alkylene-Z-aryl,
[0047] -alkylene-Z-alkenyl, and
[0048] -alkyl or alkenyl substituted by one or more substituents
selected from the group consisting of:
[0049] --OH,
[0050] -halogen,
[0051] --N(R.sub.6).sub.2,
[0052] --C(R.sub.7)--N(R.sub.6).sub.2,
[0053] --S(O).sub.2--N(R.sub.6).sub.2,
[0054] --N(R.sub.6)--C(R.sub.7)--C.sub.1-10 alkyl,
[0055] --N(R.sub.6)--S(O).sub.2--C.sub.1-10 alkyl,
[0056] --C(O)--C.sub.1-10 alkyl,
[0057] --C(O)--O--C.sub.1-10 alkyl,
[0058] --N.sub.3,
[0059] -aryl,
[0060] -heteroaryl,
[0061] -heterocyclyl,
[0062] --C(O)-aryl, and
[0063] --C(O)-heteroaryl;
[0064] each R.sub.6 is independently selected from the group
consisting of hydrogen, alkyl, and arylalkylenyl;
[0065] each R.sub.7 is independently selected from the group
consisting of .dbd.O and .dbd.S; and
[0066] Z is selected from the group consisting of --O-- and
--S(O).sub.0-2--.
[0067] In some embodiments of Formula I, R'" is R or R.sub.3 when n
is 1, R or one R and one R.sub.3 when n is 2, or R when n is 3 to
4; wherein:
[0068] R is selected from the group consisting of alkyl, alkenyl,
alkoxy, halogen, fluoroalkyl, hydroxy, amino, alkylamino, and
dialkylamino;
[0069] R.sub.3 is selected from the group consisting of:
[0070] -Z'-R.sub.4',
[0071] -Z'-X'--R.sub.4',
[0072] -Z'-X'--Y'--R.sub.4', and
[0073] -Z'-X'--R.sub.5';
[0074] Z' is a bond or --O--;
[0075] X' is selected from the group consisting of alkylene,
alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene
wherein the alkylene, alkenylene, and alkynylene groups can be
optionally interrupted or terminated by arylene, heteroarylene, or
heterocyclylene and optionally interrupted by one or more --O--
groups;
[0076] Y' is selected from the group consisting of:
[0077] --S(O).sub.0-2--,
[0078] --S(O).sub.2--N(R.sub.11)--,
[0079] --C(R.sub.7)--,
[0080] --C(R.sub.7)--O--,
[0081] --O--C(R.sub.7)--,
[0082] --O--C(O)--O--,
[0083] --N(R.sub.11)-Q-,
[0084] --C(R.sub.7)--N(R.sub.11)--,
[0085] --O--C(R.sub.7)--N(R.sub.11)--,
[0086] --C(R.sub.7)--N(OR.sub.12)--, 7
[0087] R.sub.4' is selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl,
alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl
wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,
aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl
groups can be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of
alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro,
hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy,
heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl,
amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in
the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;
[0088] R.sub.5' is selected from the group consisting of: 8
[0089] each R.sub.7 is independently selected from the group
consisting of .dbd.O and .dbd.S;
[0090] each R.sub.8 is independently C.sub.2-7 alkylene;
[0091] R.sub.10 is C.sub.3-8 alkylene;
[0092] each R.sub.11 is independently selected from the group
consisting of hydrogen, C.sub.10 alkyl, C.sub.2-10 alkenyl,
C.sub.1-10 alkoxyC.sub.2-10 alkylenyl, and arylC.sub.1-10
alkylenyl;
[0093] R.sub.12 is selected from the group consisting of hydrogen
and alkyl;
[0094] A' is selected from the group consisting of --CH.sub.2--,
--O--, --C(O)--, --S(O).sub.0-2--, and --N(R.sub.4')--;
[0095] Q is selected from the group consisting of a bond,
--C(R.sub.7)--, --C(R.sub.7)--C(R.sub.7)--, --S(O).sub.2--,
--C(R.sub.7)--N(R.sub.11)--W-- -, --S(O).sub.2--N(R.sub.11)--,
--C(R.sub.7)--O--, and --C(R.sub.7)--N(OR.sub.12)--;
[0096] V is selected from the group consisting of --C(R.sub.7)--,
--O--C(R.sub.7)--, --N(R.sub.11)--C(R.sub.7)--, and
--S(O).sub.2--;
[0097] W is selected from the group consisting of a bond, --C(O)--,
and --S(O).sub.2--; and
[0098] c and d are independently integers from 1 to 6 with the
proviso that c+d is .ltoreq.7, and when A' is --O-- or
--N(R.sub.4')-- then c and d are independently integers from 2 to
4.
[0099] The present invention also provides 1-amino
6,7,8,9-tetrahydro 1H-imidazoquinoline compounds of the following
Formula II: 9
[0100] wherein:
[0101] each R.sub.A is independently selected from the group
consisting of:
[0102] halogen,
[0103] hydroxy,
[0104] alkyl,
[0105] alkenyl,
[0106] haloalkyl,
[0107] alkoxy,
[0108] alkylthio,
[0109] --NH.sub.2.
[0110] --NH(alkyl), and
[0111] --N(alkyl).sub.2;
[0112] n is an integer from 0 to 4;
[0113] R.sub.1' is selected from the group consisting of hydrogen
and alkyl;
[0114] R.sub.1 is selected from the group consisting of:
[0115] --R.sub.4,
[0116] --Y--R.sub.4,
[0117] --X--R.sub.5,
[0118] --X--N(R.sub.6)--Y--R.sub.4,
[0119] --X--C(R.sub.7)--N(R.sub.6)--R.sub.4, and
[0120] --X--O--R.sub.4;
[0121] or R.sub.1' and R.sub.1 together with the nitrogen atom to
which they are bonded can join to form a group selected from the
group consisting of: 10
[0122] R.sub.4 is selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl wherein
the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl
groups can be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of
alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,
mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy,
heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl,
heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino,
dialkylamino, and in the case of alkyl, alkenyl, alkynyl, and
heterocyclyl, oxo, with the proviso that when R.sub.4 is a
substituted alkyl group and the substituent contains a hetero atom
which bonds directly to the alkyl group then the alkyl group
contains at least two carbons between the substituent and the
nitrogen atom to which R.sub.1 is bonded;
[0123] R.sub.5 is selected from the group consisting of: 11
[0124] each R.sub.6 is independently selected from the group
consisting of hydrogen, alkyl, and arylalkylenyl;
[0125] R.sub.7 is selected from the group consisting of .dbd.O and
.dbd.S;
[0126] R.sub.8 is C.sub.2-7 alkylene;
[0127] A is selected from the group consisting of --CH(R.sub.6)--,
--O--, --N(R.sub.6)--, --N(Y--R.sub.4)--, and
--N(X--N(R.sub.6)--Y--R.sub.4)--;
[0128] X is C.sub.2-20 alkylene;
[0129] Y is selected from the group consisting of --C(R.sub.7)--,
--C(R.sub.7)--O--, --S(O).sub.2--, --S(O).sub.2--N(R.sub.6)--, and
--C(R.sub.7)--N(R.sub.9)--; wherein R.sub.9 is selected from the
group consisting of hydrogen, alkyl, and arylalkylenyl; or R.sub.9
and R.sub.4 together with the nitrogen atom to which R.sub.9 is
bonded can join to form the group 12
[0130] a and b are independently integers from 1 to 4 with the
proviso that when A is --O--, --N(R.sub.6)--, --N(Y--R.sub.4)--, or
--N(X--N(R.sub.6)--Y--R.sub.4)-- then a and b are independently
integers from 2 to 4; and
[0131] R" is hydrogen or a non-interfering substituent;
[0132] or a pharmaceutically acceptable salt thereof.
[0133] The present invention also provides compounds of the
following Formula I-1: 13
[0134] wherein:
[0135] R.sub.1' is selected from the group consisting of hydrogen
and alkyl;
[0136] R.sub.1 is selected from the group consisting of:
[0137] --R.sub.4,
[0138] --Y--R.sub.4,
[0139] --X--R.sub.5,
[0140] --X--N(R.sub.6)--Y--R.sub.4,
[0141] --X--C(R.sub.7)--N(R.sub.6)--R.sub.4, and
[0142] --X--O--R.sub.4;
[0143] or R.sub.1' and R.sub.1 together with the nitrogen atom to
which they are bonded can join to form a group selected from the
group consisting of: 14
[0144] R.sub.2 is selected from the group consisting of:
[0145] -hydrogen,
[0146] -alkyl,
[0147] -alkenyl,
[0148] -aryl,
[0149] -heteroaryl,
[0150] -heterocyclyl,
[0151] -alkylene-Z-alkyl,
[0152] -alkylene-Z-aryl,
[0153] -alkylene-Z-alkenyl, and
[0154] -alkyl or alkenyl substituted by one or more substituents
selected from the group consisting of:
[0155] --OH,
[0156] -halogen,
[0157] --N(R.sub.6).sub.2,
[0158] --C(R.sub.7)--N(R.sub.6).sub.2,
[0159] --S(O).sub.2--N(R).sub.2,
[0160] --N(R.sub.6)--C(R.sub.7)--C.sub.1-10 alkyl,
[0161] --N(R.sub.6)--S(O).sub.2--C.sub.1-10 alkyl,
[0162] --C(O)--C.sub.1-10 alkyl,
[0163] --C(O)--O--C.sub.1-10 alkyl,
[0164] --N.sub.3,
[0165] -aryl,
[0166] -heteroaryl,
[0167] -heterocyclyl,
[0168] --C(O)-aryl, and
[0169] --C(O)-heteroaryl;
[0170] R.sub.3 is selected from the group consisting of:
[0171] -Z'-X'--R.sub.4',
[0172] -Z'-X'--Y'--R.sub.4', and
[0173] -Z'-X'--R.sub.5';
[0174] each R is independently selected from the group consisting
of alkyl, alkenyl, alkoxy, halogen, fluoroalkyl, hydroxy, amino,
alkylamino, and dialkylamino;
[0175] n is an integer from 0 to 4;
[0176] m is 0 or 1; with the proviso that when m is 1, then n is 0
or 1;
[0177] R.sub.4 is selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl wherein
the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl
groups can be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of
alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,
mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy,
heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl,
heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino,
dialkylamino, and in the case of alkyl, alkenyl, alkynyl, and
heterocyclyl, oxo, with the proviso that when R.sub.4 is a
substituted alkyl group and the substituent contains a hetero atom
which bonds directly to the alkyl group then the alkyl group
contains at least two carbons between the substituent and the
nitrogen atom to which R.sub.1 is bonded;
[0178] R.sub.5 is selected from the group consisting of: 15
[0179] X is C.sub.2-20 alkylene;
[0180] Y is selected from the group consisting of --C(R.sub.7)--,
--C(R.sub.7)--O--, --S(O).sub.2--, --S(O).sub.2--N(R)--, and
C--(R.sub.7)--N(R.sub.9)--; wherein R.sub.9 is selected from the
group consisting of hydrogen, alkyl, and arylalkylenyl; or R.sub.9
and R.sub.4 together with the nitrogen atom to which R.sub.9 is
bonded can join to form the group 16
[0181] Z is selected from the group consisting of --O-- and
--S(O).sub.0-2--;
[0182] A is selected from the group consisting of --CH(R.sub.6)--,
--O--, --N(R.sub.6)--, --N(Y--R.sub.4)--, and
--N(X--N(R.sub.6)--Y--R.sub.4)--;
[0183] a and b are independently integers from 1 to 4 with the
proviso that when A is --O--, --N(R.sub.6)--, --N(Y--R.sub.4)--, or
--N(X--N(R.sub.6)--Y--R.sub.4)-- then a and b are independently
integers from 2 to 4;
[0184] R.sub.4' is selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl,
alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl
wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,
aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,
heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl
groups can be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of
alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro,
hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy,
heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl,
amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in
the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;
[0185] R.sub.5' is selected from the group consisting of: 17
[0186] X' is selected from the group consisting of alkylene,
alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene
wherein the alkylene, alkenylene, and alkynylene groups can be
optionally interrupted or terminated by arylene, heteroarylene, or
heterocyclylene and optionally interrupted by one or more --O--
groups;
[0187] Y' is selected from the group consisting of: 18
[0188] Z' is a bond or --O--;
[0189] A' is selected from the group consisting of --CH.sub.2--,
--O--, --C(O)--, --S(O).sub.0-2--, and --N(R.sub.4')--;
[0190] Q is selected from the group consisting of a bond,
--C(R.sub.7)--, --C(R.sub.7)--C(R.sub.7)--, --S(O).sub.2--,
--C(R.sub.7)--N(R.sub.11)--W-- -, --S(O).sub.2--N(R.sub.11)--,
--C(R.sub.7)--O--, and --C(R.sub.7)--N(O.sub.R.sub.12)--;
[0191] V is selected from the group consisting of --C(R.sub.7)--,
--O--C(.sub.7)--, --N(R.sub.11)--C(R.sub.7)--, and
--S(O).sub.2--;
[0192] W is selected from the group consisting of a bond, --C(O)--,
and --S(O).sub.2--;
[0193] c and d are independently integers from 1 to 6 with the
proviso that c+d is .ltoreq.7, and when A' is --O-- or
--N(R.sub.4')-- then c and d are independently integers from 2 to
4;
[0194] each R.sub.6 is independently selected from the group
consisting of hydrogen, alkyl, and arylalkylenyl;
[0195] each R.sub.7 is independently selected from the group
consisting of .dbd.O and .dbd.S;
[0196] each R.sub.8 is independently C.sub.2-7 alkylene;
[0197] R.sub.10 is C.sub.3-8 alkylene;
[0198] each R.sub.11 is independently selected from the group
consisting of hydrogen, C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.1-10alkoxyC.sub.1-- 10alkylenyl, and arylC.sub.1-10alkylenyl;
and
[0199] R.sub.12 is selected from the group consisting of hydrogen
and alkyl;
[0200] or a pharmaceutically acceptable salt thereof.
[0201] In some embodiments of Formula I-1, R.sub.1 is selected from
the group consisting of --R.sub.4, --Y--R.sub.4, and
--X--N(R.sub.6)--Y--R.su- b.4 wherein Y is --C(R.sub.7)--,
--S(O).sub.2--, or --C(R.sub.7)--N(R.sub.9)--.
[0202] In certain embodiments of Formula I-1, R.sub.1 is selected
from the group consisting of hydrogen, alkyl, alkenyl,
arylalkylenyl, arylalkenylenyl, heteroarylalkylenyl,
heteroarylalkenylenyl, aminoalkylenyl, alkoxyalkylenyl, acyl,
alkylsulfonylaminoalkylenyl, arylsulfonylaminoalkylenyl,
alkylaminocarbonyl, arylaminocarbonyl,
(arylalkylenyl)aminoalkylenyl, and
arylaminocarbonylaminoalkylenyl.
[0203] In certain embodiments of Formula I-1, R.sub.1 is selected
from the group consisting of hydrogen, methyl, isopropyl, butyl,
2-methylpropyl, 1-ethylpropyl, 3-methylbutyl, cyclohexyl, benzyl,
3-phenylpropyl, cinnamyl, furan-2-ylmethyl, and
--CH.sub.2CH.sub.2CH.sub.2--NHR.sub.13, wherein R.sub.13 is
selected from the group consisting of methanesulfonyl,
phenylsulfonyl, benzyl, isopropylaminocarbonyl, and
phenylaminocarbonyl.
[0204] In some embodiments of Formula I-1, R.sub.1' is
hydrogen.
[0205] In some embodiments of Formula I-1, R.sub.1 and R.sub.1' are
each independently alkyl.
[0206] In some embodiments of Formula I-1, R.sub.1 and R.sub.1'
join to form the group: 19
[0207] In some embodiments of Formula I-1, R.sub.2 is selected from
the group consisting of hydrogen, alkyl, and alkoxyalkylenyl, and
in certain embodiments R.sub.2 is selected from the group
consisting of hydrogen, methyl, propyl, butyl, 2-methoxyethyl, and
ethoxymethyl.
[0208] In some embodiments of Formula I-1, n is 0.
[0209] In some embodiments of Formula I-1, n is 0, and R.sub.3 is
selected from the group consisting of -Z'-R.sub.4',
-Z'-X'--R.sub.4', and -Z'--X'--Y'--R.sub.4', and in certain
embodiments R.sub.3 is selected from the group consisting of
2-(pyridin-3-yl)ethyl, pyridinyl, hydroxymethylpyridinyl,
ethoxyphenyl, (morpholine-4-carbonyl)phenyl,
2-(methanesulfonylamino)ethoxy, and benzyloxy.
[0210] The present invention also provides compounds of the
following Formula (I-2): 20
[0211] wherein:
[0212] R.sub.B is selected from the group consisting of alkyl,
alkoxy, halogen, hydroxy, and trifluoromethyl;
[0213] n is an integer from 0 to 4;
[0214] R.sub.1' is selected from the group consisting of hydrogen
and alkyl;
[0215] R.sub.1 is selected from the group consisting of:
[0216] --R.sub.4,
[0217] --Y--R.sub.4,
[0218] --X--R.sub.5,
[0219] --X--N(R.sub.6)--Y--R.sub.4,
[0220] --X--C(R.sub.7)--N(R.sub.6)--R.sub.4, and
[0221] --X--O--R.sub.4;
[0222] or R.sub.1' and R.sub.1 together with the nitrogen atom to
which they are bonded can join to form a group selected from the
group consisting of: 21
[0223] R.sub.2 is selected from the group consisting of:
[0224] -hydrogen,
[0225] -alkyl,
[0226] -alkenyl,
[0227] -aryl,
[0228] -heteroaryl,
[0229] -heterocyclyl,
[0230] -alkylene-Z-alkyl,
[0231] -alkylene-Z-aryl,
[0232] -alkylene-Z-alkenyl, and
[0233] -alkyl or alkenyl substituted by one or more substituents
selected from the group consisting of:
[0234] --OH,
[0235] -halogen,
[0236] --N(R).sub.2,
[0237] --C(R.sub.7)--N(R).sub.2,
[0238] --S(O).sub.2--N(R.sub.6).sub.2,
[0239] --N(R.sub.6)--C(R.sub.7)--C.sub.1-10 alkyl,
[0240] --N(R.sub.6)--S(O).sub.2--C.sub.1-10 alkyl,
[0241] --C(O)--C.sub.1-10 alkyl,
[0242] --C(O)--O--C.sub.1-10 alkyl,
[0243] --N.sub.3,
[0244] -aryl,
[0245] -heteroaryl,
[0246] -heterocyclyl,
[0247] --C(O)-aryl, and
[0248] --C(O)-heteroaryl;
[0249] R.sub.4 is selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl wherein
the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl
groups can be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of
alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,
mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy,
heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl,
heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino,
dialkylamino, and in the case of alkyl, alkenyl, alkynyl, and
heterocyclyl, oxo, with the proviso that when R.sub.4 is a
substituted alkyl group and the substituent contains a hetero atom
which bonds directly to the alkyl group then the alkyl group
contains at least two carbons between the substituent and the
nitrogen atom to which R.sub.1 is bonded;
[0250] R.sub.5 is selected from the group consisting of: 22
[0251] each R.sub.6 is independently selected from the group
consisting of hydrogen, alkyl, and arylalkylenyl;
[0252] each R.sub.7 is independently selected from the group
consisting of .dbd.O and .dbd.S;
[0253] R.sub.8 is C.sub.2-7 alkylene;
[0254] A is selected from the group consisting of --CH(R.sub.6)--,
--O--, --N(R.sub.6)--, --N(Y--R.sub.4)--, and
--N(X--N(R.sub.6)--Y--R.sub.4)--;
[0255] X is C.sub.2-20 alkylene;
[0256] Y is selected from the group consisting of --C(R.sub.7)--,
--C(R.sub.7)--O--, --S(O).sub.2--, --S(O).sub.2--N(R.sub.6)--, and
--C(R.sub.7)--N(R.sub.9)--; wherein R.sub.9 is selected from the
group consisting of hydrogen, alkyl, and arylalkylenyl; or R.sub.9
and R.sub.4 together with the nitrogen atom to which R.sub.9 is
bonded can join to form the group 23
[0257] Z is selected from the group consisting of --O-- and
--S(O).sub.0-2--; and
[0258] a and b are independently integers from 1 to 4 with the
proviso that when A is --O--, --N(R.sub.6)--, --N(Y--R.sub.4)--, or
--N(X--N(R.sub.6)--Y--R.sub.4)-- then a and b are independently
integers from 2 to 4;
[0259] or a pharmaceutically acceptable salt thereof.
[0260] In some embodiments of Formula I-2, R.sub.1 is selected from
the group consisting of --R.sub.4, --Y--R.sub.4, and
--X--N(R.sub.6)--Y--R.su- b.4 wherein Y is --C(R.sub.7)--,
--S(O).sub.2--, or --C(R.sub.7)--N(R.sub.9)--.
[0261] In certain embodiments of Formula I-2, R.sub.1 is selected
from the group consisting of hydrogen, alkyl, alkenyl,
arylalkylenyl, arylalkenylenyl, heteroarylalkylenyl,
heteroarylalkenylenyl, aminoalkylenyl, alkoxyalkylenyl, acyl,
alkylsulfonylaminoalkylenyl, arylsulfonylaminoalkylenyl,
alkylaminocarbonyl, arylaminocarbonyl,
(arylalkylenyl)aminoalkylenyl, and
arylaminocarbonylaminoalkylenyl.
[0262] In certain embodiments of Formula I-2, R.sub.1 is selected
from the group consisting of hydrogen, methyl, isopropyl, butyl,
2-methylpropyl, 1-ethylpropyl, 3-methylbutyl, cyclohexyl, benzyl,
cinnamyl, furan-2-ylmethyl, and
--CH.sub.2CH.sub.2CH.sub.2--NHR.sub.13, wherein R.sub.13 is
selected from the group consisting of methanesulfonyl,
phenylsulfonyl, benzyl, and phenylaminocarbonyl.
[0263] In some embodiments of Formula I-2, R.sub.1' is
hydrogen.
[0264] In some embodiments of Formula I-2, R.sub.1 and R.sub.1' are
each independently alkyl.
[0265] In some embodiments of Formula I-2, R.sub.1 and R.sub.1'
join to form the group: 24
[0266] In some embodiments of Formula I-2, R.sub.2 is selected from
the group consisting of hydrogen, alkyl, and alkoxyalkylenyl, and
in certain embodiments R.sub.2 is selected from the group
consisting of hydrogen, butyl, 2-methoxyethyl, and
ethoxymethyl.
[0267] In some embodiments of Formula I-2, n is 0.
[0268] In some embodiments of Formula I-2, n is 1, and R is halogen
or hydroxy.
[0269] The present invention also provides compounds of the
following Formula (I-3): 25
[0270] wherein:
[0271] R.sub.B is selected from alkyl, alkoxy, halogen, hydroxy,
and trifluoromethyl;
[0272] n is an integer from 0 to 4;
[0273] R.sub.1' is selected from hydrogen and alkyl;
[0274] R.sub.1 is selected from:
[0275] --R.sub.4,
[0276] --Y--R.sub.4,
[0277] --X--R.sub.5,
[0278] --X--N(R.sub.6)--Y--R.sub.4,
[0279] --X--CR.sub.7--N(R.sub.6)--R.sub.4, and
[0280] --X--O--R.sub.4;
[0281] or R.sub.1' and R.sub.1 together with the nitrogen atom to
which they are bonded can join to form a group selected from:
26
[0282] R.sub.2A is selected from:
[0283] -hydrogen,
[0284] -alkyl,
[0285] -alkenyl,
[0286] -aryl,
[0287] -heteroaryl,
[0288] -alkylene-Z-alkyl,
[0289] -alkylene-Z-aryl,
[0290] -alkylene-Z- alkenyl, and
[0291] -alkyl or alkenyl substituted by one or more substituents
selected from:
[0292] --OH,
[0293] -halogen,
[0294] --N(R).sub.2,
[0295] --CR.sub.7--N(R.sub.6).sub.2,
[0296] --SO.sub.2--N(R).sub.2,
[0297] --N(R.sub.6)--CR.sub.7--C.sub.1-10 alkyl,
[0298] --N(R.sub.6)--SO.sub.2--C.sub.1-10 alkyl,
[0299] --C(O)--C.sub.1-10 alkyl,
[0300] --C(O)--O--C.sub.1-10 alkyl,
[0301] --N.sub.3,
[0302] -aryl,
[0303] -heteroaryl,
[0304] -heterocyclyl,
[0305] --C(O)-aryl, and
[0306] --C(O)-heteroaryl;
[0307] R.sub.4 is selected from hydrogen, alkyl, alkenyl, alkynyl,
aryl, heteroaryl, and heterocyclyl wherein the alkyl, alkenyl,
alkynyl, aryl, heteroaryl, and heterocyclyl groups can be
unsubstituted or substituted by one or more substituents
independently selected from alkyl, alkoxy, haloalkyl, haloalkoxy,
halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl,
aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy,
heterocyclyl, heterocyclylalkylenyl, amino, alkylamino,
(arylalkylenyl)amino, dialkylamino, and in the case of alkyl,
alkenyl, alkynyl, and heterocyclyl, oxo, with the proviso that when
R.sub.4 is a substituted alkyl group and the substituent contains a
hetero atom which bonds directly to the alkyl group then the alkyl
group contains at least two carbons between the substituent and the
nitrogen atom to which R.sub.1 is bonded;
[0308] R.sub.5 is selected from: 27
[0309] R.sub.6 is selected from hydrogen, alkyl, and
arylalkylenyl;
[0310] R.sub.7 is selected from .dbd.O and .dbd.S;
[0311] R.sub.8 is C.sub.2-7 alkylene;
[0312] R.sub.9 is selected from hydrogen, alkyl, and arylalkylenyl,
or R.sub.9 and R.sub.4 together with the nitrogen atom to which
R.sub.9 is bonded can join to form the group 28
[0313] A is selected from --CHR.sub.6--, --O--, --N(R.sub.6)--,
--N(Y--R.sub.4)--, and --N(X--N(R.sub.6)--Y--R.sub.4)--;
[0314] X is C.sub.2-20 alkylene;
[0315] Y is selected from --CR.sub.7--, --SO.sub.2--,
--SO.sub.2--N(R.sub.6)--, and --CR.sub.7--N(R.sub.9)--;
[0316] Z is selected from --O-- and --S(O).sub.0-2--;
[0317] a and b are independently integers from 1 to 4 with the
proviso that when A is --O--, --N(R.sub.6)--, --N(Y--R.sub.4)--, or
--N(X--N(R.sub.6)--Y--R.sub.4)-- then a and b are independently
integers from 2 to 4;
[0318] and pharmaceutically acceptable salts thereof.
[0319] In some embodiments of Formula I-3, R.sub.1 is selected from
--R.sub.4, --Y--R.sub.4, and --X--N(R.sub.6)--Y--R.sub.4 wherein Y
is --CR.sub.7--, --SO.sub.2--, or --CR.sub.7--N(R.sub.9)--.
[0320] In certain embodiments of Formula I-3, R.sub.1 is selected
from the group consisting of hydrogen, alkyl, alkenyl,
arylalkylenyl, arylalkenylenyl, heteroarylalkylenyl,
heteroarylalkenylenyl, aminoalkylenyl, alkoxyalkylenyl, acyl,
alkylsulfonylaminoalkylenyl, arylsulfonylaminoalkylenyl,
alkylaminocarbonyl, arylaminocarbonyl,
(arylalkylenyl)aminoalkylenyl, and
arylaminocarbonylaminoalkylenyl.
[0321] In certain embodiments of Formula I-3, R.sub.1 is selected
from hydrogen, isopropyl, butyl, cyclohexyl, benzyl, cinnamyl, and
--CH.sub.2CH.sub.2CH.sub.2--NHR.sub.13, wherein R.sub.13 is
selected from methanesulfonyl, phenylsulfonyl, benzyl, and
phenylaminocarbonyl.
[0322] In some embodiments of Formula I-3, R.sub.1' is
hydrogen.
[0323] In some embodiments of Formula I-3, R.sub.2A is selected
from hydrogen, alkyl, and alkoxyalkylenyl, and in certain
embodiments R.sub.2A is selected from hydrogen, butyl, methoxyethyl
(e.g., 2-methoxyethyl), and ethoxymethyl.
[0324] In some embodiments of Formula I-3, n is 0.
[0325] The present invention also provides compounds of the
following Formula (II-1): 29
[0326] wherein:
[0327] each R.sub.A is independently selected from the group
consisting of:
[0328] halogen,
[0329] hydroxy,
[0330] alkyl,
[0331] alkenyl,
[0332] haloalkyl,
[0333] alkoxy,
[0334] alkylthio,
[0335] --NH.sub.2,
[0336] --NH(alkyl), and
[0337] --N(alkyl).sub.2;
[0338] n is an integer from 0 to 4;
[0339] R.sub.1' is selected from the group consisting of hydrogen
and alkyl;
[0340] R.sub.1 is selected from the group consisting of:
[0341] --R.sub.4,
[0342] --Y--R.sub.4,
[0343] --X--R.sub.5,
[0344] --X--N(R.sub.6)--Y--R.sub.4,
[0345] --X--C(R.sub.7)--N(R.sub.6)--R.sub.4, and
[0346] --X--O--R.sub.4;
[0347] or R.sub.1' and R.sub.1 together with the nitrogen atom to
which they are bonded can join to form a group selected from the
group consisting of: 30
[0348] R.sub.2 is selected from the group consisting of:
[0349] -hydrogen,
[0350] -alkyl,
[0351] -alkenyl,
[0352] -aryl,
[0353] -heteroaryl,
[0354] -heterocyclyl,
[0355] -alkylene-Z-alkyl,
[0356] -alkylene-Z-aryl,
[0357] -alkylene-Z-alkenyl, and
[0358] -alkyl or alkenyl substituted by one or more substituents
selected from the group consisting of:
[0359] --OH,
[0360] -halogen,
[0361] --N(R.sub.6).sub.2,
[0362] --C(R.sub.7)--N(R.sub.6).sub.2,
[0363] --S(O).sub.2--N(R.sub.6).sub.2,
[0364] --N(R.sub.6)--CR.sub.7)--C.sub.1-10 alkyl,
[0365] --N(R.sub.6)--S(O).sub.2--C.sub.1-10 alkyl,
[0366] --C(O)--C.sub.1-10 alkyl,
[0367] --C(O)--O--C.sub.1-10 alkyl,
[0368] --N.sub.3,
[0369] -aryl,
[0370] -heteroaryl,
[0371] -heterocyclyl,
[0372] --C(O)-aryl, and
[0373] --C(O)-heteroaryl;
[0374] R.sub.4 is selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl wherein
the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl
groups can be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of
alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,
mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy,
heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl,
heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino,
dialkylamino, and in the case of alkyl, alkenyl, alkynyl, and
heterocyclyl, oxo, with the proviso that when R.sub.4 is a
substituted alkyl group and the substituent contains a hetero atom
which bonds directly to the alkyl group then the alkyl group
contains at least two carbons between the substituent and the
nitrogen atom to which R.sub.1 is bonded;
[0375] R.sub.5 is selected from the group consisting of: 31
[0376] each R.sub.6 is independently selected from the group
consisting of hydrogen, alkyl, and arylalkylenyl;
[0377] each R.sub.7 is independently selected from the group
consisting of .dbd.O and .dbd.S;
[0378] R.sub.8 is C.sub.2-7 alkylene;
[0379] A is selected from the group consisting of --CH(R.sub.6)--,
--O--, --N(R.sub.6)--, --N(Y--R.sub.4)--, and
--N(X--N(R.sub.6)--Y--R.sub.4)--;
[0380] X is C.sub.2-20 alkylene;
[0381] Y is selected from the group consisting of --C(R.sub.7)--,
--C(R.sub.7)--O--, --S(O).sub.2--, --S(O).sub.2--N(R.sub.6)--, and
--C(R.sub.7)--N(R.sub.9)--; wherein R.sub.9 is selected from the
group consisting of hydrogen, alkyl, and arylalkylenyl; or R.sub.9
and R.sub.4 together with the nitrogen atom to which R.sub.9 is
bonded can join to form the group 32
[0382] Z is selected from the group consisting of --O-- and
--S(O).sub.0-2--; and
[0383] a and b are independently integers from 1 to 4 with the
proviso that when A is --O--, --N(R.sub.6)--, --N(Y--R.sub.4)--, or
--N(X--N(R.sub.6)--Y--R.sub.4)-- then a and b are independently
integers from 2 to 4;
[0384] or a pharmaceutically acceptable salt thereof.
[0385] In some embodiments of Formula II-1, R.sub.1 is selected
from the group consisting of --R.sub.4, --Y--R.sub.4, and
--X--N(R.sub.6)--Y--R.su- b.4 wherein Y is --C(R.sub.7)--,
--S(O).sub.2--, or --C(R.sub.7)--N(R.sub.9)--.
[0386] In certain embodiments of Formula II-1, R.sub.1 is selected
from the group consisting of hydrogen, alkyl, alkenyl,
arylalkylenyl, arylalkenylenyl, heteroarylalkylenyl,
heteroarylalkenylenyl, aminoalkylenyl, alkoxyalkylenyl, acyl,
alkylsulfonylaminoalkylenyl, arylsulfonylaminoalkylenyl,
alkylaminocarbonyl, arylaminocarbonyl,
(arylalkylenyl)aminoalkylenyl, and
arylaminocarbonylaminoalkylenyl.
[0387] In certain embodiments of Formula II-1, R.sub.1 is selected
from the group consisting of hydrogen, methyl, isopropyl, butyl,
2-methylpropyl, 1-ethylpropyl, 3-methylbutyl, cyclohexyl, benzyl,
cinnamyl, furan-2-ylmethyl, and
--CH.sub.2CH.sub.2CH.sub.2--NHR.sub.13, wherein R.sub.13 is
selected from the group consisting of methanesulfonyl,
phenylsulfonyl, benzyl, and phenylaminocarbonyl.
[0388] In certain embodiments of Formula II-1, R.sub.1 is selected
from the group consisting of hydrogen, methyl, isopropyl, butyl,
2-methylpropyl, l-ethylpropyl, 3-methylbutyl, cyclohexyl, benzyl,
3-phenylpropyl, cinnamyl, furan-2-ylmethyl, and
--CH.sub.2CH.sub.2CH.sub.- 2--NHR.sub.13, wherein R.sub.13 is
selected from the group consisting of methanesulfonyl,
phenylsulfonyl, benzyl, isopropylaminocarbonyl, and
phenylaminocarbonyl.
[0389] In some embodiments of Formula II-1, R.sub.1' is
hydrogen.
[0390] In some embodiments of Formula II-1, R.sub.1 and R.sub.1'
are each independently alkyl.
[0391] In some embodiments of Formula II-1, R.sub.1 and R.sub.1'
join to form the group: 33
[0392] In some embodiments of Formula II-1, R.sub.2 is selected
from the group consisting of hydrogen, alkyl, and alkoxyalkylenyl,
in certain embodiments R.sub.2 is selected from the group
consisting of hydrogen, butyl, 2-methoxyethyl, and ethoxymethyl,
and in certain embodiments R.sub.2 is selected from the group
consisting of hydrogen, methyl, propyl, butyl, 2-methoxyethyl, and
ethoxymethyl.
[0393] In some embodiments of Formula II-1, n is 0.
[0394] The present invention also provides compounds that are
useful as intermediates in the synthesis of compounds of Formula I,
I-1, I-2, I-3, II, and/or II-1. These intermediate compounds have
the structural Formulas VII, IX, X, XLII, and XLIII described
below.
[0395] The present invention provides intermediate compounds of the
following Formula (VII): 34
[0396] wherein:
[0397] each R.sub.B is independently selected from the group
consisting of alkyl, alkoxy, halogen, hydroxy, and
trifluoromethyl;
[0398] n is an integer from 0 to 4;
[0399] R.sub.2 is selected from the group consisting of:
[0400] -hydrogen,
[0401] -alkyl,
[0402] -alkenyl,
[0403] -aryl,
[0404] -heteroaryl,
[0405] -heterocyclyl,
[0406] -alkylene-Z-alkyl,
[0407] -alkylene-Z-aryl,
[0408] -alkylene-Z-alkenyl, and
[0409] -alkyl or alkenyl substituted by one or more substituents
selected from the group consisting of:
[0410] --OH,
[0411] -halogen,
[0412] --N(R.sub.6).sub.2,
[0413] --C(R.sub.7)--N(R.sub.6).sub.2,
[0414] --S(O).sub.2--N(R.sub.6).sub.2,
[0415] --N(R.sub.6)--C(R.sub.7)--C.sub.1-10 alkyl,
[0416] --N(R.sub.6)--S(O).sub.2--C.sub.1-10 alkyl,
[0417] --C(O)--C.sub.1-10 alkyl,
[0418] --C(O)--O--C.sub.1-10 alkyl,
[0419] --N.sub.3,
[0420] -aryl,
[0421] -heteroaryl,
[0422] -heterocyclyl,
[0423] --C(O)-aryl, and
[0424] --C(O)-heteroaryl;
[0425] each R.sub.6 is independently selected from the group
consisting of hydrogen, alkyl, and arylalkylenyl;
[0426] R.sub.7 is selected from the group consisting of .dbd.O and
.dbd.S; and
[0427] Z is selected from the group consisting of --O-- and
--S(O).sub.0-2--;
[0428] or a pharmaceutically acceptable salt thereof.
[0429] The present invention also provides intermediate compounds
of the following Formula (IX): 35
[0430] wherein:
[0431] each R.sub.B is independently selected from the group
consisting of alkyl, alkoxy, halogen, hydroxy, and
trifluoromethyl;
[0432] n is an integer from 0 to 4;
[0433] R.sub.1' is hydrogen or alkyl;
[0434] R.sub.1 is selected from the group consisting of:
[0435] --R.sub.4,
[0436] --Y--R.sub.4,
[0437] --X--R.sub.5,
[0438] --X--N(R.sub.6)--Y--R.sub.4,
[0439] --X--C(R.sub.7)--N(R.sub.6)--R.sub.4, and
[0440] --X--O--R.sub.4;
[0441] or R.sub.1' and R.sub.1 together with the nitrogen atom to
which they are bonded can join to form a group selected from the
group consisting of: 36
[0442] R.sub.2 is selected from the group consisting of:
[0443] -hydrogen,
[0444] -alkyl,
[0445] -alkenyl,
[0446] -aryl,
[0447] -heteroaryl,
[0448] -heterocyclyl,
[0449] -alkylene-Z-alkyl,
[0450] -alkylene-Z-aryl,
[0451] -alkylene-Z-alkenyl, and
[0452] -alkyl or alkenyl substituted by one or more substituents
selected from the group consisting of:
[0453] --OH,
[0454] -halogen,
[0455] --N(R.sub.6).sub.2,
[0456] --C(R.sub.7)--N(R.sub.6).sub.2,
[0457] --S(O).sub.2--N(R.sub.6).sub.2,
[0458] --N(R.sub.6)--C(R.sub.7)--C.sub.1-10 alkyl,
[0459] --N(R.sub.6)--S(O).sub.2--C.sub.1-10 alkyl,
[0460] --C(O)--C.sub.1-10 alkyl,
[0461] --C(O)--O--C.sub.1-10 alkyl,
[0462] --N.sub.3,
[0463] -aryl,
[0464] -heteroaryl,
[0465] -heterocyclyl,
[0466] --C(O)-aryl, and
[0467] --C(O)-heteroaryl;
[0468] R.sub.4 is selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl wherein
the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl
groups can be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of
alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,
mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy,
heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl,
heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino,
dialkylamino, and in the case of alkyl, alkenyl, alkynyl, and
heterocyclyl, oxo, with the proviso that when R.sub.4 is a
substituted alkyl group and the substituent contains a hetero atom
which bonds directly to the alkyl group then the alkyl group
contains at least two carbons between the substituent and the
nitrogen atom to which R.sub.1 is bonded;
[0469] R.sub.5 is selected from the group consisting of 37
[0470] each R.sub.6 is independently selected from the group
consisting of hydrogen, alkyl, and arylalkylenyl;
[0471] each R.sub.7 is independently selected from the group
consisting of .dbd.O and .dbd.S;
[0472] R.sub.8 is C.sub.2-7 alkylene;
[0473] A is selected from the group consisting of --CH(R.sub.6)--,
--O--, --N(R.sub.6)--, --N(Y--R.sub.4)--, and
--N(X--N(R)--Y--R.sub.4)--;
[0474] X is C.sub.2-20 alkylene;
[0475] Y is selected from the group consisting of --C(R.sub.7)--,
--C(R.sub.7)--O--, --S(O).sub.2--, --S(O).sub.2--N(R.sub.6)--, and
--C(R.sub.7)--N(R.sub.9)--; wherein R.sub.9 is selected from the
group consisting of hydrogen, alkyl, and arylalkylenyl; or R.sub.9
and R.sub.4 together with the nitrogen atom to which R.sub.9 is
bonded can join to form the group 38
[0476] Z is selected from the group consisting of --O-- and
--S(O).sub.0-2--; and
[0477] a and b are independently integers from 1 to 4 with the
proviso that when A is --O--, --N(R.sub.6)--, --N(Y--R.sub.4)--, or
--N(X--N(R.sub.6)--Y--R.sub.4)-- then a and b are independently
integers from 2 to 4;
[0478] or a pharmaceutically acceptable salt thereof.
[0479] The present invention also provides intermediate compounds
of the following Formula (X): 39
[0480] wherein:
[0481] each R.sub.B is independently selected from the group
consisting of alkyl, alkoxy, halogen, hydroxy, and
trifluoromethyl;
[0482] n is an integer from 0 to 4;
[0483] R.sub.1' is hydrogen or alkyl;
[0484] R.sub.1a is selected from the group consisting of:
[0485] --R.sub.4a,
[0486] --Y--R.sub.4a,
[0487] --X--R.sub.5,
[0488] --X--N(R.sub.6)--Y--R.sub.4a,
[0489] --X--C(R.sub.7)--N(R.sub.6)--R.sub.4a, and
[0490] --X--O--R.sub.4a;
[0491] or R.sub.1' and R.sub.1a together with the nitrogen atom to
which they are bonded can join to form a group selected from the
group consisting of: 40
[0492] R.sub.2a is selected from the group consisting of:
[0493] -hydrogen,
[0494] -alkyl,
[0495] -alkenyl,
[0496] -aryl,
[0497] -alkylene-Z"-alkyl,
[0498] -alkylene-Z"-aryl,
[0499] -alkylene-Z"-alkenyl, and
[0500] -alkyl or alkenyl substituted by one or more substituents
selected from the group consisting of:
[0501] --OH,
[0502] -halogen,
[0503] --N(R.sub.6).sub.2,
[0504] --C(R.sub.7)--N(R.sub.6).sub.2,
[0505] --S(O).sub.2--N(R.sub.6).sub.2,
[0506] --N(R.sub.6)--C(R.sub.7)--C.sub.1-10 alkyl,
[0507] --N(R.sub.6)--S(O).sub.2--C.sub.1-10 alkyl,
[0508] --C(O)--C.sub.1-10 alkyl,
[0509] --C(O)--O--C.sub.1-10 alkyl,
[0510] --N.sub.3,
[0511] -aryl,
[0512] -heterocyclyl, and
[0513] --C(O)-aryl;
[0514] R.sub.4a is selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, aryl, and heterocyclyl wherein the alkyl,
alkenyl, alkynyl, aryl, and heterocyclyl groups can be
unsubstituted or substituted by one or more substituents
independently selected from the group consisting of alkyl, alkoxy,
haloalkyl, haloalkoxy, halogen, nitro, hydroxy, cyano, carboxy,
formyl, aryl, aryloxy, arylalkoxy, heterocyclyl,
heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino,
dialkylamino, and in the case of alkyl, alkenyl, alkynyl, and
heterocyclyl, oxo, with the proviso that when R.sub.4a is a
substituted alkyl group and the substituent contains a hetero atom
which bonds directly to the alkyl group then the alkyl group
contains at least two carbons between the substituent and the
nitrogen atom to which R.sub.1 is bonded;
[0515] R.sub.5 is selected from the group consisting of 41
[0516] each R.sub.6 is independently selected from the group
consisting of hydrogen, alkyl, and arylalkylenyl;
[0517] each R.sub.7 is independently selected from the group
consisting of .dbd.O and .dbd.S;
[0518] R.sub.8 is C.sub.2-7 alkylene;
[0519] A is selected from the group consisting of --CH(R.sub.6)--,
--O--, --N(R.sub.6)--, --N(Y--R.sub.4)--, and
--N(X--N(R.sub.6)--Y--R.sub.4)--;
[0520] X is C.sub.2-20 alkylene;
[0521] Y is selected from the group consisting of --C(R.sub.7)--,
--C(R.sub.7)--O--, --S(O).sub.2--, --S(O).sub.2--N(R.sub.6)--, and
--C(R.sub.7)--N(R.sub.9)--; wherein R.sub.9 is selected from the
group consisting of hydrogen, alkyl and arylalkylenyl, or R.sub.9
and R.sub.4 together with the nitrogen atom to which R.sub.9 is
bonded can join to form the group 42
[0522] Z" is selected from the group consisting of --O-- and
--S(O).sub.2--; and
[0523] a and b are independently integers from 1 to 4 with the
proviso that when A is --O--, --N(R.sub.6)--, --N(Y--R.sub.4)--, or
--N(X--N(R.sub.6)--Y--R.sub.4)-- then a and b are independently
integers from2to4;
[0524] or a pharmaceutically acceptable salt thereof.
[0525] The present invention also provides intermediate compounds
of the following Formula (XLII): 43
[0526] wherein:
[0527] R is selected from the group consisting of alkyl, alkenyl,
alkoxy, halogen, fluoroalkyl, hydroxy, amino, alkylamino, and
dialkylamino;
[0528] l is 0 or 1;
[0529] R.sub.2 is selected from the group consisting of:
[0530] -hydrogen,
[0531] -alkyl,
[0532] -alkenyl,
[0533] -aryl,
[0534] -heteroaryl,
[0535] -heterocyclyl,
[0536] -alkylene-Z-alkyl,
[0537] -alkylene-Z-aryl,
[0538] -alkylene-Z-alkenyl, and
[0539] -alkyl or alkenyl substituted by one or more substituents
selected from the group consisting of:
[0540] --OH,
[0541] -halogen,
[0542] --N(R.sub.6).sub.2.
[0543] --C(R.sub.7)--N(R.sub.6).sub.2,
[0544] --S(O).sub.2--N(R.sub.6).sub.2,
[0545] --N(R.sub.6)--C(R.sub.7)--C.sub.1-10 alkyl,
[0546] --N(R)--S(O).sub.2--C.sub.1-10 alkyl,
[0547] --C(O)--C.sub.1-10 alkyl,
[0548] --C(O)--O--C.sub.1-10 alkyl,
[0549] --N.sub.3,
[0550] -aryl,
[0551] -heteroaryl,
[0552] -heterocyclyl,
[0553] --C(O)-aryl, and
[0554] --C(O)-heteroaryl;
[0555] each R.sub.6 is independently selected from the group
consisting of hydrogen, alkyl, and arylalkylenyl;
[0556] R.sub.7 is selected from the group consisting of .dbd.O and
.dbd.S; and
[0557] Z is selected from the group consisting of --O-- and
--S(O).sub.0-2--;
[0558] or a pharmaceutically acceptable salt thereof.
[0559] The present invention also provides intermediate compounds
of the following Formula (XLIII): 44
[0560] wherein:
[0561] R is selected from the group consisting of alkyl, alkenyl,
alkoxy, halogen, fluoroalkyl, hydroxy, amino, alkylamino, and
dialkylamino;
[0562] l is 0 or 1;
[0563] R.sub.1' is hydrogen or alkyl;
[0564] R.sub.1 is selected from the group consisting of:
[0565] --R.sub.4,
[0566] --Y--R.sub.4,
[0567] --X--R.sub.5,
[0568] --X--N(R.sub.6)--Y--R.sub.4,
[0569] --X--C(R.sub.7)--N(R.sub.6)--R.sub.4, and
[0570] --X--O--R.sub.4;
[0571] or R.sub.1' and R.sub.1 together with the nitrogen atom to
which they are bonded can join to form a group selected from the
group consisting of: 45
[0572] R.sub.2 is selected from the group consisting of:
[0573] -hydrogen,
[0574] -alkyl,
[0575] -alkenyl,
[0576] -aryl,
[0577] -heteroaryl,
[0578] -heterocyclyl,
[0579] -alkylene-Z-alkyl,
[0580] -alkylene-Z-aryl,
[0581] -alkylene-Z-alkenyl, and
[0582] -alkyl or alkenyl substituted by one or more substituents
selected from the group consisting of:
[0583] --OH,
[0584] -halogen,
[0585] --N(R.sub.6).sub.2,
[0586] --C(R.sub.7)--N(R.sub.6).sub.2,
[0587] --S(O).sub.2--N(R.sub.6).sub.2,
[0588] --N(R.sub.6)--C(R.sub.7)--C.sub.1-10 alkyl,
[0589] --N(R.sub.6)--S(O).sub.2--C.sub.1-10 alkyl,
[0590] --C(O)--C.sub.1-10 alkyl,
[0591] --C(O)--O--C.sub.1-10 alkyl,
[0592] --N.sub.3,
[0593] -aryl,
[0594] -heteroaryl,
[0595] -heterocyclyl,
[0596] --C(O)-aryl, and
[0597] --C(O)-heteroaryl;
[0598] R.sub.4 is selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl wherein
the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl
groups can be unsubstituted or substituted by one or more
substituents independently selected from the group consisting of
alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,
mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy,
heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl,
heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino,
dialkylamino, and in the case of alkyl, alkenyl, alkynyl, and
heterocyclyl, oxo, with the proviso that when R.sub.4 is a
substituted alkyl group and the substituent contains a hetero atom
which bonds directly to the alkyl group then the alkyl group
contains at least two carbons between the substituent and the
nitrogen atom to which R.sub.1 is bonded;
[0599] R.sub.5 is selected from the group consisting of 46
[0600] each R.sub.6 is independently selected from the group
consisting of hydrogen, alkyl, and arylalkylenyl;
[0601] each R.sub.7 is independently selected from the group
consisting of .dbd.O and .dbd.S;
[0602] R.sub.8 is C.sub.2-7 alkylene;
[0603] A is selected from the group consisting of --CH(R.sub.6)--,
--O--, --N(R.sub.6)--, --N(Y--R.sub.4)--, and
--N(X--N(R.sub.6)--Y--R.sub.4)--,
[0604] X is C.sub.2-20 alkylene;
[0605] Y is selected from the group consisting of --C(R.sub.7)--,
--C(R.sub.7)--O--, --S(O).sub.2--, --S(O).sub.2--N(R.sub.6)--, and
--C(R.sub.7)--N(R.sub.9)--; wherein R.sub.9 is selected from the
group consisting of hydrogen, alkyl, and arylalkylenyl; or R.sub.9
and R.sub.4 together with the nitrogen atom to which R.sub.9 is
bonded can join to form the group 47
[0606] Z is selected from the group consisting of --O-- and
--S(O).sub.0-2--; and
[0607] a and b are independently integers from 1 to 4 with the
proviso that when A is --O--, --N(R.sub.6)--, --N(Y--R.sub.4)--, or
--N(X--N(R.sub.6)--Y--R.sub.4)-- then a and b are independently
integers from 2 to 4;
[0608] or a pharmaceutically acceptable salt thereof.
[0609] Herein, "non-interfering" means that the ability of the
compound or salt to modulate (e.g., induce or inhibit) the
biosynthesis of one or more cytokines is not destroyed by the
non-interfering substitutent. Illustrative non-interfering R"
groups include those described above for R.sub.2 in Formulas I-1,
I-2, and II-1, and for R.sub.2A in Formula I-3. Illustrative
non-interfering R'" groups include those described above for R and
R.sub.3 in Formula I-1, and for R.sub.B in Formulas I-2 and
I-3.
[0610] As used herein, the terms "alkyl," "alkenyl," "alkynyl" and
the prefix "alk-" are inclusive of both straight chain and branched
chain groups and of cyclic groups, i.e. cycloalkyl and
cycloalkenyl. Unless otherwise specified, these groups contain from
1 to 20 carbon atoms, with alkenyl groups containing from 2 to 20
carbon atoms, and alkynyl groups containing from 2 to 20 carbon
atoms. In some embodiments, these groups have a total of up to 10
carbon atoms, up to 8 carbon atoms, up to 6 carbon atoms, or up to
4 carbon atoms. Cyclic groups can be monocyclic or polycyclic and
preferably have from 3 to 10 ring carbon atoms. Exemplary cyclic
groups include cyclopropyl, cyclopropylmethyl, cyclopentyl,
cyclohexyl, adamantyl, and substituted and unsubstituted bornyl,
norbornyl, and norbornenyl.
[0611] Unless otherwise specified, "alkylene," "alkenylene," and
"alkynylene" are the divalent forms of the "alkyl," "alkenyl," and
"alkynyl" groups defined above. Likewise, "alkylenyl,"
"alkenylenyl," and "alkynylenyl" are the divalent forms of the
"alkyl," "alkenyl," and "alkynyl" groups defined above. For
example, an arylalkylenyl group comprises an alkylene moiety to
which an aryl group is attached.
[0612] The term "haloalkyl" is inclusive of alkyl groups that are
substituted by one or more halogen atoms, including perfluorinated
groups. This is also true of other groups that include the prefix
"halo-". Examples of suitable haloalkyl groups are chloromethyl,
trifluoromethyl, and the like. Similarly, the term "fluoroalkyl" is
inclusive of groups that are substituted by one or more fluorine
atoms, including perfluorinated groups (e.g., trifluoromethyl).
[0613] The term "aryl" as used herein includes carbocyclic aromatic
rings or ring systems. Examples of aryl groups include phenyl,
naphthyl, biphenyl, fluorenyl and indenyl.
[0614] The term "heteroatom" refers to the atoms O, S, or N.
[0615] The term "heteroaryl" includes aromatic rings or ring
systems that contain at least one ring heteroatom (e.g., O, S, N).
Suitable heteroaryl groups include furyl, thienyl, pyridyl,
quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl,
pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl,
benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl,
pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl,
naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl,
pyrazinyl, 1-oxidopyridyl, pyridazinyl, triazinyl, tetrazinyl,
oxadiazolyl, thiadiazolyl, and so on.
[0616] The term "heterocyclyl" includes non-aromatic rings or ring
systems that contain at least one ring heteroatom (e.g., O, S, N)
and includes all of the fully saturated and partially unsaturated
derivatives of the above mentioned heteroaryl groups. Exemplary
heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl,
morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl,
thiazolidinyl, imidazolidinyl, isothiazolidinyl, tetrahydropyranyl,
quinuclidinyl, homopiperidinyl, homopiperazinyl, and the like.
[0617] The terms "arylene," "heteroarylene," and "heterocyclylene"
are the divalent forms of the "aryl," "heteroaryl," and
"heterocyclyl" groups defined above. Likewise, "arylenyl,"
"heteroarylenyl," and "heterocyclylenyl" are the divalent forms of
the "aryl," "heteroaryl," and "heterocyclyl" groups defined above.
For example, an alkylarylenyl group comprises an arylene moiety to
which an alkyl group is attached.
[0618] When a group or substituent is present more that once in any
Formula described herein, each group or substituent is
independently selected, whether specifically stated or not.
[0619] The invention is inclusive of the compounds described herein
and salts thereof in any of their pharmaceutically acceptable
forms, including isomers such as diastereomers and enantiomers,
solvates, polymorphs, and the like. In particular, if a compound is
optically active, the invention specifically includes each of the
compound's enantiomers as well as racemic mixtures of the
enantiomers.
[0620] Preparation of the Compounds
[0621] Compounds of the invention can be prepared according to
Reaction Scheme I wherein R, R.sub.1a, R.sub.2a, and n are as
defined above.
[0622] In step (1) of Reaction Scheme I, a
4-chloro-3-nitroquinoline of Formula III is reacted with tert-butyl
carbazate or an alternate carbazate to provide a carbazate compound
of Formula IV. The reaction can be carried out by adding tert-butyl
carbazate to a solution of a compound of Formula III in a suitable
solvent such as anhydrous dichloromethane in the presence of a base
such as triethylamine. The reaction can be run at ambient
temperature. The product or a pharmaceutically acceptable salt
thereof can be isolated by conventional methods. Many compounds of
Formula III are known or can be prepared using known synthetic
methods, see for example, U.S. Pat. Nos. 4,689,338; 5,175,296;
5,367,076; and 5,389,640; and the documents cited therein.
Tertiary-butyl carbazate is commercially available (for example,
from Aldrich, Milwaukee, Wis.). Many alternate carbazate reagents
(for example, benzyl carbazate) may be prepared using known
synthetic methods.
[0623] In step (2) of Reaction Scheme I a carbazate compound of
Formula IV is reduced to provide a compound of Formula V. The
reduction can be carried out using a conventional heterogeneous
hydrogenation catalyst such as platinum on carbon or palladium on
carbon. For some compounds of Formula IV, for example, compounds in
which R is halogen, a platinum catalyst is preferred. The reaction
can be conveniently carried out on a Parr apparatus in a suitable
solvent such as toluene and/or isopropanol. The product or a
pharmaceutically acceptable salt thereof can be isolated by
conventional methods.
[0624] Other reduction processes may be used for the reduction in
step (2). For example, an aqueous solution of sodium dithionite can
be added to a solution or suspension of the compound of Formula IV
in a suitable solvent such as ethanol or isopropanol. The reaction
can be carried out at an elevated temperature, for example at
reflux, or at ambient temperature.
[0625] In step (3) of Reaction Scheme I a compound of Formula V is
(i) reacted with an acyl halide of Formula R.sub.2aC(O)Cl or
R.sub.2aC(O)Br and then (ii) cyclized to provide a 1H-imidazo
compound of Formula VI. In part (i) the acyl halide is added to a
solution of a compound of Formula V in a suitable solvent such as
anhydrous dichloromethane in the presence of a base such as
triethylamine. The reaction can be run at a reduced temperature,
for example, 0.degree. C., or at ambient temperature. In part (ii)
the product of part (i) is heated in an alcoholic solvent in the
presence of a base. For example, the product of part (i) is
refluxed in ethanol in the presence of excess triethylamine or is
heated with methanolic ammonia.
[0626] Alternatively, step (3) can be carried out by reacting a
compound of Formula V with a carboxylic acid or an equivalent
thereof. Suitable equivalents to carboxylic acid include
orthoesters and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid
or equivalent is selected such that it will provide the desired
R.sub.2a substituent in a compound of Formula VI. For example,
triethyl orthoformate will provide a compound where R.sub.2a is
hydrogen, and triethyl orthovalerate will provide a compound where
R.sub.2a is butyl. The reaction can be run in the absence of
solvent or in an inert solvent such as anhydrous toluene. The
reaction is run with sufficient heating to drive off any alcohol or
water formed as a byproduct of the reaction. Optionally a catalyst
such as pyridine hydrochloride can be included. The product or a
pharmaceutically acceptable salt thereof can be isolated by
conventional methods.
[0627] In step (4) of Reaction Scheme I, the tert-butoxycarbonyl or
alternate oxycarbonyl group is removed from a 1H-imidazo compound
of Formula VI by hydrolysis under acidic conditions to provide a
1H-imidazo[4,5-c]quinolin-l-amine of Formula VIIa or a salt (for
example, hydrochloride salt) thereof. For example, a compound of
Formula VI is dissolved in 1.5M HCl in ethanol and heated to
reflux. The product or a pharmaceutically acceptable salt thereof
can be isolated by conventional methods.
[0628] In step (5a) of Reaction Scheme I, a
1H-imidazo[4,5-c]quinolin-1-am- ine of Formula VIIa or a salt
thereof is treated with a ketone, aldehyde, or corresponding ketal
or acetal thereof, under acidic conditions to provide a compound of
Formula VIII. For example, a ketone is added to a solution of the
hydrochloride salt of a compound of Formula VIIa in a suitable
solvent such as isopropanol in the presence of an acid or acid
resin, for example, DOWEX W50-X1 acid resin. The ketone, aldehyde,
or corresponding ketal or acetal thereof, is selected with R.sub.i
and R.sub.ii groups that will provide the desired R.sub.1a
substituent in a 1H-imidazo[4,5-c]quinolin-1-amine compound of
Formula IXa. For example, acetone will provide a compound where
R.sub.1a is isopropyl, and benzaldehyde will provide a compound
where R.sub.1a is benzyl. The reaction is run with sufficient
heating to drive off the water formed as a byproduct of the
reaction. The product or a pharmaceutically acceptable salt thereof
can be isolated by conventional methods.
[0629] In step (6) of Reaction Scheme I, a compound of Formula VIII
is reduced to provide a 1H-imidazo[4,5-c]quinolin-1-amine compound
of Formula IXa. The reaction can be carried out by adding sodium
borohydride to a solution of a compound of Formula VIII in a
suitable solvent, for example, methanol. The reaction can be run at
ambient temperature. The product or a pharmaceutically acceptable
salt thereof can be isolated by conventional methods.
[0630] Alternatively, in step (5b) of Reaction Scheme I, a
1H-imidazo[4,5-c]quinolin-1-amine of Formula VIIa can be treated
with a ketone and a borohydride under acidic conditions to provide
a 1H-imidazo[4,5-c]quinolin-1-amine compound of Formula IXa. For
example, the hydrochloride salt of a
1H-imidazo[4,5-c]quinolin-1-amine of Formula VIIa, dissolved in a
suitable solvent such as 1,2-dichloroethane, can be treated with a
ketone and sodium triacetoxyborohydride at room temperature. The
product or a pharmaceutically acceptable salt thereof can be
isolated by conventional methods.
[0631] In step (7) of Reaction Scheme I, a
1H-imidazo[4,5-c]quinolin-1-ami- ne compound of Formula IXa is
oxidized to provide an N-oxide of Formula Xa using a conventional
oxidizing agent that is capable of forming N-oxides. The reaction
is carried out by treating a solution of a compound of Formula IXa
in a suitable solvent such as chloroform or dichloromethane with
3-chloroperoxybenzoic acid at ambient temperature. The product or a
pharmaceutically acceptable salt thereof can be isolated by
conventional methods.
[0632] In step (8) of Reaction Scheme I, an N-oxide of Formula Xa
is aminated to provide a 1H-imidazo[4,5-c]quinoline-1,4-diamine of
the Formula Ia, which is a subgenus of compounds of the Formulas I,
I-1, I-2, and I-3. The reaction is carried out in two parts. In
part (i) a compound of Formula Xa is reacted with an acylating
agent. Suitable acylating agents include alkyl- or arylsulfonyl
chorides (e.g., benzenesulfonyl choride, methanesulfonyl choride,
and p-toluenesulfonyl chloride). In part (ii) the product of part
(i) is reacted with an excess of an aminating agent. Suitable
aminating agents include ammonia (e.g. in the form of ammonium
hydroxide) and ammonium salts (e.g., ammonium carbonate, ammonium
bicarbonate, ammonium phosphate). The reaction can be carried out
by dissolving a compound of Formula Xa in a suitable solvent such
as dichloromethane, adding ammonium hydroxide to the solution, and
then adding p-toluenesulfonyl chloride. The product or a
pharmaceutically acceptable salt thereof can be isolated using
conventional methods.
[0633] Alternatively, the oxidation of step (7) and the amination
of step (8) can be carried out sequentially without isolating the
product of the oxidation to provide a
1H-imidazo[4,5-c]quinoline-1,4-diamine of the Formula Ia. In step
(7), after the 1H-imidazo[4,5-c]quinolin-1-amine compound of
Formula IXa is consumed by reaction with 3-chloroperoxybenzoic acid
as described in step (7), the aminating and acylating agents are
added to the reaction mixture as in step (8). The product or a
pharmaceutically acceptable salt thereof can be isolated using
conventional methods. 48
[0634] Compounds of the invention can be prepared according to
Reaction Scheme II wherein R, R.sub.1, R.sub.2a and n are as
defined above.
[0635] In step (1) of Reaction Scheme II, a 1H-imidazo compound of
Formula VI is oxidized to provide an N-oxide of Formula XI using
the method of step (7) in Reaction Scheme I. The product or a
pharmaceutically acceptable salt thereof can be isolated by
conventional methods.
[0636] In step (2) of Reaction Scheme II, an N-oxide of Formula XI
is aminated using the method of step (8) in Reaction Scheme I to
provide a 4-amino compound of the Formula XIIa. The product or a
pharmaceutically acceptable salt thereof can be isolated using
conventional methods.
[0637] In step (3) of Reaction Scheme II, the tert-butoxycarbonyl
or alternate oxycarbonyl group is removed from a 4-amino compound
of the Formula XIIa using the method of step (4) in Reaction Scheme
I to provide a 1H-imidazo[4,5-c]quinoline-1,4-diamine of Formula
XIIIa or a salt (for example, hydrochloride salt) thereof. The
product or a pharmaceutically acceptable salt thereof can be
isolated by conventional methods.
[0638] In step (4a) of Reaction Scheme II, a
1H-imidazo[4,5-c]quinoline-1,- 4-diamine of Formula XIIIa is
treated with a ketone, aldehyde, or corresponding ketal or acetal
thereof, using the method of step (5a) in Reaction Scheme I to
provide a compound of Formula XIVa. The ketone, aldehyde, or
corresponding ketal or acetal thereof, is selected with R.sub.i and
R.sub.ii groups that will provide the desired R.sub.1 substituent
in a 1H-imidazo[4,5-c]quinoline-1,4-diamine compound of Formula Ib.
The product or a pharmaceutically acceptable salt thereof can be
isolated by conventional methods.
[0639] In step (5) of Reaction Scheme II, a compound of Formula
XIVa is reduced to provide a 1H-imidazo[4,5-c]quinolin-1-amine
compound of Formula Ib using the method of step (6) in Reaction
Scheme I. The product or a pharmaceutically acceptable salt thereof
can be isolated by conventional methods.
[0640] Alternatively, in step (4b) of Reaction Scheme II, a
1H-imidazo[4,5-c]quinoline-1,4-diamine of Formula XIIIa can be
treated with a ketone and a borohydride using the method of step
(5b) of Reaction Scheme I to provide a
1H-imidazo[4,5-c]quinolin-1-amine compound of Formula Ib, which is
a subgenus of compounds of the Formulas I, I-1, I-2, and I-3. The
product or a pharmaceutically acceptable salt thereof can be
isolated by conventional methods. 49
[0641] Compounds of the invention can be prepared according to
Reaction Scheme III wherein R, R.sub.1', R.sub.1a, R.sub.2a, and n
are as defined above.
[0642] In step (1) of Reaction Scheme III, a
4-chloro-3-nitroquinoline of Formula III is reacted with a
hydrazino compound of Formula XVa to provide a compound of Formula
XVI. The reaction can be carried out by adding the hydrazino
compound of Formula XVa to a solution of a compound of Formula III
in a suitable solvent such as anhydrous dichloromethane in the
presence of a base such as triethylamine. The reaction can be run
at ambient temperature. The product or a pharmaceutically
acceptable salt thereof can be isolated by conventional methods.
Many hydrazino compounds of Formula XVa are commercially available;
others can be readily prepared using known synthetic methods.
[0643] In step (2) of Reaction Scheme III, a compound of Formula
XVI is reduced to provide a compound of Formula XVII using the
methods of step (2) in Reaction Scheme I. The product or a
pharmaceutically acceptable salt thereof can be isolated by
conventional methods.
[0644] In step (3) of Reaction Scheme III, a compound of formula
XVII is cyclized using the methods of step (3) in Reaction Scheme I
to provide a 1H-imidazo[4,5-c]quinolin-1-amine compound of Formula
IXb. The product of step (i) (described in step (3) of Reaction
Scheme I) can be isolated to provide a compound of the following
formula: 50
[0645] In part (ii) the product of part (i) can be refluxed in
suitable solvent such as toluene in the presence of pyridine
hydrochloride. The product or a pharmaceutically acceptable salt
thereof can be isolated by conventional methods.
[0646] In step (4) of Reaction Scheme III, a
1H-imidazo[4,5-c]quinolin-1-a- mine compound of Formula IXb is
oxidized to provide an N-oxide of Formula X using the method of
step (7) in Reaction Scheme I. The product or a pharmaceutically
acceptable salt thereof can be isolated by conventional
methods.
[0647] In step (5) of Reaction Scheme III, an N-oxide of Formula X
is aminated using the method of step (8) in Reaction Scheme I to
provide a 1H-imidazo[4,5-c]quinoline-1,4-diamine of the Formula Ic,
which is a subgenus of compounds of the Formulas I, I-1, I-2, and
I-3. The product or a pharmaceutically acceptable salt thereof can
be isolated using conventional methods.
[0648] Alternatively, the oxidation of step (4) and the amination
of step (5) can be carried out sequentially without isolating the
product of the oxidation to provide a
1H-imidazo[4,5-c]quinoline-1,4-diamine of the Formula Ic. In step
(4), after the 1H-imidazo[4,5-c]quinolin-1-amine compound of
Formula IXb is consumed by reaction with 3-chloroperoxybenzoic acid
as described in step (4), the aminating and acylating agents are
added to the reaction mixture as in step (5). The product or a
pharmaceutically acceptable salt thereof can be isolated using
conventional methods. 51
[0649] Compounds of the invention can be prepared according to
Reaction Scheme IV wherein R, R.sub.1, R.sub.2 and n are as defined
above.
[0650] In step (1) of Reaction Scheme IV, a
2,4-dichloro-3-nitroquinoline of Formula XVIII is reacted with
tert-butyl carbazate or an alternate carbazate to provide a
carbazate compound of Formula XIX. The reaction can be carried out
by adding tert-butyl carbazate or an alternate carbazate to a
solution of a 2,4-dichloro-3-nitroquinoline of Formula XVIII in a
suitable solvent such as anhydrous dichloromethane in the presence
of a base such as triethylamine. The reaction can be run at ambient
temperature. The product or a pharmaceutically acceptable salt
thereof can be isolated by conventional methods. Many quinolines of
Formula XVIII are known or can be prepared using known synthetic
methods (see for example, Andre et al., U.S. Pat. No. 4,988,815 and
references cited therein).
[0651] In step (2) of Reaction Scheme IV, a carbazate compound of
Formula XIX is reduced to provide a 2-chloroquinolin-3-amine of
Formula XX using the method of step (2) in Reaction Scheme I. The
product or a pharmaceutically acceptable salt thereof can be
isolated by conventional methods.
[0652] In step (3) of Reaction Scheme IV, a
2-chloroquinolin-3-amine of Formula XX is reacted with an acyl
halide of formula R.sub.2C(O)Cl or R.sub.2C(O)Br, or a carboxylic
acid or equivalent thereof, using the methods of step (3) in
Reaction Scheme I to provide a 4-chloro-1H-imidazo[4,5-c]quinoline
of Formula XXI. The carboxylic acid or equivalent is selected such
that it provides the desired R.sub.2 substituent in compounds of
Formula XXI. The product or a pharmaceutically acceptable salt
thereof can be isolated by conventional methods.
[0653] In step (4) of Reaction Scheme IV, the tert-butoxycarbonyl
or alternate oxycarbonyl group is removed from a
4-chloro-1H-imidazo[4,5-c]q- uinoline of Formula XXI using the
method of step (4) of Reaction Scheme I to provide a
4-chloro-1H-imidazo[4,5-c]quinolin-1-amine of Formula XXII or a
salt thereof. The product or a pharmaceutically acceptable salt
thereof can be isolated by conventional methods.
[0654] In step (5a) of Reaction Scheme IV, a
4-chloro-1H-imidazo[4,5-c]qui- nolin-1-amine of Formula XXII or a
salt thereof is treated with a ketone, aldehyde, or corresponding
ketal or acetal using the method of step (5a) of Reaction Scheme I
to provide a compound of Formula XXIII. The ketone, aldehyde, or
corresponding ketal or acetal thereof, is selected with R.sub.i and
R.sub.ii groups that will provide the desired R.sub.1 substituent
in a 4-chloro-1H-imidazo[4,5-c]quinolin-1-amine compound of Formula
XXIVa. The product or a pharmaceutically acceptable salt thereof
can be isolated by conventional methods.
[0655] In step (6) of Reaction Scheme IV, a compound of Formula
XXIII is reduced using the method of step (6) in Reaction Scheme I
to provide a 4-chloro-1H-imidazo[4,5-c]quinolin-1-amine compound of
Formula XXIVa. The product or a pharmaceutically acceptable salt
thereof can be isolated by conventional methods.
[0656] Alternatively, in step (5b) of Reaction Scheme IV, a
4-chloro-1H-imidazo[4,5-c]quinolin-1-amine of Formula XXII can be
treated with a ketone and a borohydride using the method of step
(5b) in Reaction Scheme I to provide a
4-chloro-1H-imidazo[4,5-c]quinolin-1-amine compound of Formula
XXIVa. The product or a pharmaceutically acceptable salt thereof
can be isolated by conventional methods.
[0657] In step (7) of Reaction Scheme IV, a
4-chloro-1H-imidazo[4,5-c]quin- olin-1-amine of Formula XXIVa is
aminated to provide a 1H-imidazo[4,5-c]quinoline-1,4-diamine of
Formula Id, which is a subgenus of compounds of the Formulas I,
I-1, I-2, and I-3. The reaction is carried out by heating (e.g.,
125-175.degree. C.) a compound of Formula XXIVa under pressure in a
sealed reactor in the presence of a solution of ammonia in an
alkanol. The product or a pharmaceutically acceptable salt thereof
can be isolated using conventional methods. 52
[0658] Compounds of the invention can be prepared according to
Reaction Scheme V wherein R, R.sub.1, R.sub.2 and n are as defined
above.
[0659] In step (1) of Reaction Scheme V, a
4-chloro-1H-imidazo[4,5-c]quino- line of Formula XXI is aminated,
using the method of step (7) in Reaction Scheme IV, to provide a
4-amino compound of the Formula XII. The product or a
pharmaceutically acceptable salt thereof can be isolated by
conventional methods.
[0660] In step (2) of Reaction Scheme V, the tert-butoxycarbonyl or
alternate oxycarbonyl group is removed from a 4-amino compound of
the Formula XII using the method of step (4) of Reaction Scheme I
to provide a 1H-imidazo[4,5-c]quinoline-1,4-diamine of Formula XIII
or a salt thereof. The product or a pharmaceutically acceptable
salt thereof can be isolated by conventional methods.
[0661] In step (3a) of Reaction Scheme V, a
1H-imidazo[4,5-c]quinoline-1,4- -diamine of Formula XIII or a salt
thereof is treated with a ketone, aldehyde, or corresponding ketal
or acetal using the method of step (5a) of Reaction Scheme I to
provide a compound of Formula XIV. The ketone, aldehyde, or
corresponding ketal or acetal thereof, is selected with R.sub.i and
R.sub.ii groups that will provide the desired R.sub.1 substituent
in a 1H-imidazo[4,5-c]quinoline-1,4-diamine compound of Formula Id.
The product or a pharmaceutically acceptable salt thereof can be
isolated by conventional methods.
[0662] In step (4) of Reaction Scheme V, a compound of Formula XIV
is reduced using the method of step (6) in Reaction Scheme I to
provide a 1H-imidazo[4,5-c]quinoline-1,4-diamine compound of
Formula Id, which is a subgenus of compounds of the Formulas I,
I-1, I-2, and I-3. The product or a pharmaceutically acceptable
salt thereof can be isolated by conventional methods.
[0663] Alternatively, in step (3b) of Reaction Scheme V, a
1H-imidazo[4,5-c]quinoline-1,4-diamine of Formula XIII or a salt
thereof can be treated with a ketone and a borohydride using the
method of step (5b) in Reaction Scheme I to provide a
1H-imidazo[4,5-c]quinoline-1,4-dia- mine compound of Formula Id.
The product or a pharmaceutically acceptable salt thereof can be
isolated by conventional methods. 53
[0664] Compounds of the invention can also be prepared according to
Reaction Scheme VI wherein R, R.sub.1', R.sub.1, R.sub.2 and n are
as defined above.
[0665] In step (1) of Reaction Scheme VI, a
2,4-dichloro-3-nitroquinoline of Formula XVIII is reacted with a
hydrazino compound of Formula XV, using the method of step (1) in
Reaction Scheme III, to provide a compound of Formula XXV. The
product or a pharmaceutically acceptable salt thereof can be
isolated by conventional methods.
[0666] In step (2) of Reaction Scheme VI, a compound of Formula XXV
is reduced using the method of step (2) in Reaction Scheme I to
provide a compound of Formula XXVI. The product or a
pharmaceutically acceptable salt thereof can be isolated by
conventional methods.
[0667] In step (3) of Reaction Scheme VI, a compound of Formula
XXVI is reacted with an acyl halide of formula R.sub.2C(O)Cl or
R.sub.2C(O)Br, or a carboxylic acid or equivalent thereof using the
methods of step (3) in Reaction Scheme I to provide a
4-chloro-1H-imidazo[4,5-c]quinolin-1-amine compound of Formula
XXIV. The carboxylic acid or equivalent is selected such that it
provides the desired R.sub.2 substituent in a compound of Formula
XXIV. The product or a pharmaceutically acceptable salt thereof can
be isolated by conventional methods.
[0668] In step (4) of Reaction Scheme VI, a
4-chloro-1H-imidazo[4,5-c]quin- olin-1-amine compound of Formula
XXIV is aminated using the method of step (7) in Reaction Scheme IV
to provide a 1H-imidazo[4,5-c]quinoline-1,4-dia- mine of Formula
Ie, which is a subgenus of compounds of the Formulas I, I-1, I-2,
and I-3. The product or a pharmaceutically acceptable salt thereof
can be isolated by conventional methods. 54
[0669] Compounds of the invention can be prepared according to
Reaction Scheme VII wherein R, R.sub.1', R.sub.2a, R.sub.4, n, and
Y are as defined above, and X.sub.a is C.sub.1-20 alkylene.
[0670] In step (1) of Reaction Scheme VII, a
1H-imidazo[4,5-c]quinolin-1-a- mine of Formula VIIa or a salt
thereof is treated with a ketal or acetal, containing a protected
amino group, using the method of step (5a) of Reaction Scheme I to
provide a compound of Formula XXVII. The product or a
pharmaceutically acceptable salt thereof can be isolated by
conventional methods.
[0671] The amino ketal or acetal is selected with R.sub.1' and X
groups that will provide the desired R.sub.1' and X groups in a
1H-imidazo[4,5-c]quinolin-1,4-diamine of Formula XXX, XXXI, or
XXXII, which are subgenera of compounds of the Formulas I, I-1,
I-2, and I-3. For example, tert-butyl (3,3-diethoxypropyl)carbamate
will provide a compound where R.sub.1' is hydrogen and X is
ethylene. The amino group of an amino ketal or acetal can be
protected with a tert-butoxycarbonyl or an alternate oxycarbonyl
group. For example, 1-amino-3,3-diethoxypropane can be reacted with
di-tert-butyl dicarbonate in a suitable solvent such as
tetrahydrofuran (THF) in the presence of triethylamine to provide
tert-butyl (3,3-diethoxypropyl)carbamate.
[0672] In step (2) of Reaction Scheme VII, a compound of Formula
XXVII is reduced using the method of step (6) in Reaction Scheme I
to provide a compound of Formula XXVIII, which is a subgenus of
compounds of the Formula IX. The product or a pharmaceutically
acceptable salt thereof can be isolated by conventional
methods.
[0673] In step (3) of Reaction Scheme VII, a compound of Formula
XXVIII is oxidized to provide an N-oxide of Formula XXIX using the
method of step (7) in Reaction Scheme I. The product or a
pharmaceutically acceptable salt thereof can be isolated by
conventional methods.
[0674] In step (4) of Reaction Scheme VII, an N-oxide of Formula
XXIX is aminated using the method of step (8) in Reaction Scheme I
to provide a 1H-imidazo[4,5-c]quinoline-1,4-diamine of the Formula
XXX, which is a subgenus of compounds of the Formulas I, I-1, I-2,
and I-3. The product or a pharmaceutically acceptable salt thereof
can be isolated using conventional methods.
[0675] In step (5) of Reaction Scheme VII, a the
tert-butoxycarbonyl or alternate oxycarbonyl group is removed from
a 1H-imidazo[4,5-c]quinoline-- 1,4-diamine of the Formula XXX using
the method of step (4) of Reaction Scheme I to provide a
1H-imidazo[4,5-c]quinoline-1,4-diamine of the Formula XXXI, which
is a subgenus of compounds of the Formulas I, I-1, I-2, and I-3.
The product or a pharmaceutically acceptable salt thereof can be
isolated by conventional methods.
[0676] In step (6) of Reaction Scheme VII, a
1H-imidazo[4,5-c]quinoline-1,- 4-diamine of the Formula XXXI is
converted to a 1H-imidazo[4,5-c]quinoline- -1,4-diamine of Formula
XXXII using conventional methods. For example, a
1H-imidazo[4,5-c]quinoline-1,4-diamine of the Formula XXXI can
react with an acid chloride of Formula R.sub.4C(O)Cl to provide a
compound of Formula XXXII in which Y is --C(O)--. In addition, a
1H-imidazo[4,5-c]quinoline-1,4-diamine of the Formula XXXI can
react with sulfonyl chloride of Formula R.sub.4S(O).sub.2Cl or a
sulfonic anhydride of Formula (R.sub.4S(O).sub.2).sub.2O to provide
a compound of Formula XXXII in which Y is --S(O).sub.2--. Numerous
acid chlorides of Formula R.sub.4C(O)Cl, sulfonyl chlorides of
Formula R.sub.4S(O).sub.2Cl, and sulfonic anhydrides of Formula
(R.sub.4S(O).sub.2).sub.2O are commercially available; others can
be readily prepared using known synthetic methods. The reaction can
be conveniently carried out by adding the acid chloride of Formula
R.sub.4C(O)Cl, sulfonyl chloride of Formula R.sub.4S(O).sub.2Cl, or
sulfonic anhydride of Formula (R.sub.4S(O).sub.2).sub.2O to a
cooled solution of a 1H-imidazo[4,5-c]quinoline-1,4-diamine of the
Formula XXXI and a base such as triethylamine in a suitable solvent
such as chloroform, dichloromethane, or acetonitrile. The reaction
can be carried out at ambient temperature or at a sub-ambient
temperature such as 0.degree. C. The product or pharmaceutically
acceptable salt thereof can be isolated using conventional
methods.
[0677] Ureas of Formula XXXII, where Y is
--C(R.sub.7)--N(R.sub.9)--, in which R.sub.7 is .dbd.O, and R.sub.9
is as defined above, can be prepared by reacting a
1H-imidazo[4,5-c]quinoline-1,4-diamine of the Formula XXXI with
isocyanates of Formula R.sub.4N=C.dbd.O. Numerous isocyanates of
Formula R.sub.4N.dbd.C.dbd.O are commercially available; others can
be readily prepared using known synthetic methods. The reaction can
be conveniently carried out by adding the isocyanate of Formula
R.sub.4N.dbd.C.dbd.O to a cooled solution of a
1H-imidazo[4,5-c]quinoline- -1,4-diamine of the Formula XXXI in a
suitable solvent such as dichloromethane or chloroform. The
reaction can be carried out at ambient temperature or at a
sub-ambient temperature such as 0.degree. C. Alternatively, a
compound of Formula XXXI can be treated with a thioisocyanate of
Formula R.sub.4N.dbd.C.dbd.S, or a carbamoyl chloride of Formula
R.sub.4N(R.sub.9)--C(O)Cl to provide a compound of Formula XXXII,
where Y is --C(S)--N(R.sub.9)--, in which R.sub.9, is as defined
above. The product or pharmaceutically acceptable salt thereof can
be isolated using conventional methods. 55
[0678] Compounds of the invention can be prepared according to
Reaction Scheme VIII where n is as defined above; each R.sub.C is
independently selected from the group consisting of hydroxy, alkyl,
and alkoxy; and R.sub.1b and R.sub.2b are a subset of R.sub.1 and
R.sub.2, respectively, as defined above, which do not include those
groups that one skilled in the art would recognize as being
susceptible to reduction under the acidic hydrogenation conditions
in step (1). These susceptible groups include, for example,
alkenyl, alkynyl, and aryl groups, and groups bearing nitro
substituents.
[0679] In step (1) of Reaction Scheme VIII, a
1H-imidazo[4,5-c]quinolin-4-- amine of Formula If is reduced to
provide a 6,7,8,9-tetrahydro-1H-imidazo[- 4,5-c]quinolin-4-amine of
Formula IIa, which is a subgenus of compounds of the Formulas II
and II-1. The reaction can be conveniently carried out by
suspending or dissolving a compound of Formula If in
trifluoroacetic acid, adding platinum(IV) oxide, and hydrogenating
under an atmosphere of hydrogen. The reaction can be carried out in
a Parr apparatus. The product or a pharmaceutically acceptable salt
thereof can be isolated using conventional methods. 56
[0680] Compounds of the invention may be prepared according to
Reaction Scheme IX where R.sub.A, R.sub.1, R.sub.1', R.sub.2, and n
is as defined above; and each R.sub.a is independently alkyl. Steps
(1) through (4) may be carried out as described in U.S. Pat. No.
5,352,784 and documents cited therein. In step (1) the amino group
of a compound of Formula XXXIII may be acylated to provide a
compound of Formula XXXIV. The reaction may be conveniently carried
out by reacting a compound of Formula XXXIII with an alkyl malonyl
chloride in the presence of a base such as triethylamine in a
suitable solvent such as methylene chloride. The product or a
pharmaceutically acceptable salt thereof may be isolated using
conventional methods. Certain compounds of Formula XXXIII are
commercially available and others can be prepared as described in
U.S. Pat. No. 5,352,784 and documents cited therein. Alkyl malonyl
chlorides are known, some of which are commercially available, and
others can be made my known methods.
[0681] In step (2) of Reaction Scheme IX, a compound of Formula
XXXIV may be cyclized to provide a compound of Formula XXXV. The
reaction may be conveniently carried out by adding a solution of a
compound of Formula XXXIV in a suitable solvent such as THF to a
suspension of sodium hydride (or other base capable of removing a
malonyl methylene proton) in a suitable solvent such as THF. The
reaction may be run at an elevated temperature, for example the
reflux temperature. The product or a pharmaceutically acceptable
salt thereof may be isolated using conventional methods.
[0682] In step (3) of Reaction Scheme IX, a compound of Formula
XXXV may be hydrolyzed and decarboxylated to provide a compound of
Formula XXXVI. The reaction may be carried out by conventional
methods, for example, by combining a compound of Formula XXXV with
an acid, such as hydrochloric acid, with heating. The product may
be isolated using conventional methods.
[0683] In step (4) of Reaction Scheme IX, a compound of Formula
XXXVI may be nitrated to provide a compound of Formula XXXVII. The
reaction may be carried out under conventional nitration
conditions, such as by heating a compound of Formula XXXVI in the
presence of nitric acid, preferably in a solvent such acetic acid.
The product or a pharmaceutically acceptable salt thereof may be
isolated using conventional methods.
[0684] In step (5) of Reaction Scheme IX, a compound of Formula
XXXVII may be chlorinated to provide a
2,4-dichloro-3-nitro-5,6,7,8-tetrahydroquinol- ine of Formula
XXXVIII. The reaction may be carried out by combining a compound of
Formula XXXVII with a conventional chlorinating agent (e.g.,
phosphorus oxychloride, thionyl chloride, phosgene, oxalyl
chloride, or phosphorus pentachloride), optionally in solvent such
as N,N-dimethylformamide (DMF) or methylene chloride, with heating
(e.g., at the reflux temperature). The product or a
pharmaceutically acceptable salt thereof may be isolated from the
reaction mixture using conventional methods.
[0685] In step (6) of Reaction Scheme IX, a
2,4-dichloro-3-nitro-5,6,7,8-t- etrahydroquinoline of Formula
XXXVIII may be reacted with a hydrazino compound of Formula XV
(H.sub.2N--N(R.sub.1')(R.sub.1), using the method of step (1) in
Reaction Scheme III, to provide a compound of Formula XXXIX. The
product or a pharmaceutically acceptable salt thereof may be
isolated by conventional methods.
[0686] In step (7) of Reaction Scheme IX, a compound of Formula
XXXIX may be reduced using the method of step (2) in Reaction
Scheme I to provide a compound of Formula XL. The product or a
pharmaceutically acceptable salt thereof may be isolated by
conventional methods.
[0687] In step (8) of Reaction Scheme IX, a compound of Formula XL
may be reacted with an acyl halide of formula R.sub.2C(O)Cl or
R.sub.2C(O)Br, or a carboxylic acid or equivalent thereof using the
methods of step (3) in Reaction Scheme I to provide a
4-chloro-1H-imidazo[4,5-c]quinolin-1-amine compound of Formula XLI.
The carboxylic acid or equivalent may be selected such that it
provides the desired R.sub.2 substituent in a compound of Formula
II-1. The product or a pharmaceutically acceptable salt thereof may
be isolated by conventional methods.
[0688] In step (9) of Reaction Scheme IX, a
4-chloro-1H-imidazo[4,5-c]quin- olin-1-amine compound of Formula
XLI may be aminated using the method of step (7) in Reaction Scheme
IV to provide a 1H-imidazo[4,5-c]quinoline-1,- 4-diamine of Formula
II-1. The product or a pharmaceutically acceptable salt thereof may
be isolated by conventional methods. 57
[0689] For some embodiments, compounds of the invention are
prepared according to Reaction Scheme X, wherein R, R.sub.1a,
R.sub.2a, and l are as defined above; Hal is chloro, bromo, or
iodo; R.sub.3a is -Z'-R.sub.4', -Z'-X'--R.sub.4',
-Z'-X'--Y'--R.sub.4', or -Z'-X'-R.sub.5'; wherein R.sub.4', Y', X',
and R.sub.5' are as defined above; and Z' is a bond.
[0690] In step (1) of Reaction Scheme X, a
4-chloro-3-nitroquinoline of Formula XLIV is converted to a
carbazate of Formula XLV according to the method described in step
(1) of Reaction Scheme I. Compounds of Formula XLIV can be readily
prepared using known synthetic routes; see for example, U.S. Pat.
Nos. 4,689,338 (Gerster), 5,367,076 (Gerster), 6,331,539 (Crooks et
al.), 6,451,810 (Coleman et al.), 6,541,485 (Crooks et al.) and the
documents cited therein.
[0691] In steps (2) and (3) of Reaction Scheme X, a
nitro-substituted quinoline of Formula XLV is first reduced to an
amino-substituted quinoline of Formula XLVI, which is then cyclized
to a 1H-imidazoquinoline of Formula XLVII. Steps (2) and (3) of
Reaction Scheme X can be carried out as described for steps (2) and
(3) of Reaction Scheme I.
[0692] In step (4) of Reaction Scheme X, the tert-butoxycarbonyl
group of a 1H-imidazoquinoline of Formula XLVII is hydrolyzed under
acidic conditions to provide a 1H-imidazo[4,5-c]quinolin-1-amine of
Formula VIIb or a pharmaceutically acceptable salt thereof. The
reaction is conveniently carried out as described in step (4) of
Reaction Scheme I.
[0693] The 1H-imidazo[4,5-c]quinolin-1-amine of Formula VIb is then
converted to a 1H-imidazo[4,5-c]quinolin-1-amine of Formula IXc
using either a two-step procedure as shown in steps (5a) and (6) of
Reaction Scheme X or a one-step procedure as shown in step (5b).
The two-step procedure, in which a compound of Formula VIIIb is
isolated, can be carried out as described in steps (5a) and (6) of
Reaction Scheme I. In step (5a), the ketone, aldehyde, or
corresponding ketal or acetal thereof, is selected with R.sub.i and
R.sub.ii groups that will provide the desired R.sub.1a substituent
in a 1H-imidazo[4,5-c]quinolin-1-amine compound of Formula IXc.
Step (5b) of Reaction Scheme X can be carried out as described for
step (5b) of Reaction Scheme I.
[0694] In steps (7) and (8) of Reaction Scheme X, a
1H-imidazo[4,5-c]quinolin-1-amine of Formula IXc is first oxidized
to an N-oxide of Formula Xb, which is then aminated to provide a
1H-imidazo[4,5-c]quinoline-1,4-diamine of Formula Ig, which is a
subgenus of the compounds of the Formulas I, I-1, I-2, and I-3.
Steps (7) and (8) of Reaction Scheme X can be carried out according
to the procedures described in steps (7) and (8) of Reaction Scheme
I.
[0695] Step (9) of Reaction Scheme X can be carried out using known
palladium-catalyzed coupling reactions such as Suzuki coupling,
Stille coupling, Sonogashira coupling, and the Heck reaction. For
example, a 1H-imidazo[4,5-c]quinoline-1,4-diamine of Formula Ig
undergoes Suzuki coupling with a boronic acid of Formula
R.sub.3a--B(OH).sub.2, an anhydride thereof, or a boronic acid
ester of Formula R.sub.3a--B(O-alkyl).sub.2 to provide an
1H-imidazo[4,5-c]quinoline-1,4-d- iamine of Formula I-1b, a
subgenus of Formulas I and I-1, wherein R.sub.3a is -Z'-R.sub.4',
-Z'-X'--R.sub.4', -Z'-X'-Y'-R.sub.4', or -Z'-X'-R.sub.5'; -Z' is a
bond; --X'-- is alkenylene, arylene, or heteroarylene optionally
terminated by arylene or heteroarylene; and R.sub.4', Y', and
R.sub.5' are as defined above. The coupling is carried out by
combining a compound of Formula Ig with a boronic acid or an ester
or anhydride thereof in the presence of palladium (II) acetate,
triphenylphosphine, and a base such as sodium carbonate in a
suitable solvent such as n-propanol. The reaction can be carried
out at an elevated temperature (e.g., 80-100.degree. C.). Numerous
boronic acids of Formula R.sub.3a--B(OH).sub.2, anhydrides thereof,
and boronic acid esters of Formula R.sub.3a--B(O-alkyl).sub.2 are
commercially available; others can be readily prepared using known
synthetic methods. See, for example, Li, W. et al, J. Org. Chem.,
67, 5394-5397 (2002). The product of Formula I-1b or a
pharmaceutically acceptable salt thereof can be isolated by
conventional methods.
[0696] The Heck reaction can also be used in step (9) of Reaction
Scheme X to provide compounds of Formula I-1b, wherein R.sub.3a is
-Z'-X'--R.sub.4' or -Z'-X'--Y'--R.sub.4'; -Z' is a bond; --X'-- is
alkenylene optionally terminated by arylene or heteroarylene; and
R.sub.4' and Y' are as defined above. The Heck reaction is carried
out by coupling a 1H-imidazo[4,5-c]quinoline-1,4-diamine of Formula
Ig with a vinyl-substituted arylene or heteroarylene compound.
Several vinyl-substituted arylene or heteroarylene compounds, such
as 2-vinylpyridine, 3-vinylpyridine, and 4-vinylpyridine, are
commercially available; others can be prepared by known methods.
The reaction is conveniently carried out by combining the
1H-imidazo[4,5-c]quinoline-1,4-- diamine of Formula Ig and the
vinyl-substituted compound in the presence of palladium (II)
acetate, triphenylphosphine or tri-ortho-tolylphosphine- , and a
base such as triethylamine in a suitable solvent such as
acetonitrile or toluene. The reaction can be carried out at an
elevated temperature such as 100-120.degree. C. under an inert
atmosphere. The compound or pharmaceutically acceptable salt
thereof can be isolated using conventional methods.
[0697] Compounds of Formula I-1b, wherein R.sub.3a is
-Z'-X'--R.sub.4' or -Z'-X'--Y'--R.sub.4', -Z' is a bond and --X'--
is alkenylene optionally terminated by arylene or heteroarylene,
may be reduced to provide compounds wherein --X'-- is alkylene
optionally terminated by arylene or heteroarylene. For example,
compounds wherein R.sub.3a is a 2-(pyridin-3-yl)ethyl group may be
prepared in this manner. The reduction can be carried out by
hydrogenation using a conventional heterogeneous hydrogenation
catalyst such as palladium on carbon. The reaction can conveniently
be carried out on a Parr apparatus in a suitable solvent such as
ethanol, methanol, or mixtures thereof. The compound or
pharmaceutically acceptable salt thereof can be isolated using
conventional methods. 58
[0698] For some embodiments, compounds of the invention can be
prepared according to Reaction Scheme XI where R, R.sub.1a,
R.sub.2a, and 1 are as defined above; Boc is tert-butoxycarbonyl;
R.sub.3b is -Z'-R.sub.4', -Z'-X'--R.sub.4', -Z'-X'--Y'--R.sub.4',
or -Z'-X'--R.sub.5'; X', Y', and R.sub.4' are as defined above; and
Z' is --O--.
[0699] In step (1) of Reaction Scheme XI, a benzyloxyaniline of
Formula XLVIII is treated with the condensation product generated
from 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) and
triethyl orthoformate to provide an imine of Formula XLIX. The
reaction is conveniently carried out by adding a solution of a
benzyloxyaniline of Formula XLVIII to a heated mixture of Meldrum's
acid and triethyl orthoformate and heating the reaction at an
elevated temperature such as 45.degree. C. The product can be
isolated using conventional methods.
[0700] In step (2) of Reaction Scheme XI, an imine of Formula XLIX
undergoes thermolysis and cyclization to provide a
benzyloxyquinolin-4-ol of Formula L. The reaction is conveniently
carried out in a heat transfer fluid such as DOWTHERM A heat
transfer fluid at a temperature between 200 and 250.degree. C. The
product can be isolated using conventional methods.
[0701] In step (3) of Reaction Scheme XI, a benzyloxyquinolin-4-ol
of Formula L is nitrated under conventional nitration conditions to
provide a benzyloxy-3-nitroquinolin-4-ol of Formula LI. The
reaction is conveniently carried out by adding nitric acid to the
benzyloxyquinolin-4-ol of Formula L in a suitable solvent such as
propionic acid and heating the mixture at an elevated temperature
such as 125.degree. C. The product can be isolated using
conventional methods.
[0702] In step (4) of Reaction Scheme XI, a
benzyloxy-3-nitroquinolin-4-ol of Formula LI is chlorinated using
conventional chlorination chemistry to provide a
benzyloxy-4-chloro-3-nitroquinoline of Formula LII. The reaction is
conveniently carried out by treating the
benzyloxy-3-nitroquinolin-4-ol of Formula LI with phosphorous
oxychloride in a suitable solvent such as DMF. The reaction can be
carried out at ambient temperature or at an elevated temperature
such as 100.degree. C., and the product can be isolated using
conventional methods.
[0703] In step (5) of Reaction Scheme XI, a
benzyloxy-4-chloro-3-nitroquin- oline of Formula LII is converted
to a carbazate of Formula LIII. The reaction is conveniently
carried out as described in step (1) of Reaction Scheme I.
[0704] In steps (6) and (7) of Reaction Scheme XI, a
nitro-substituted quinoline of Formula LIII is first reduced to an
amino-substituted quinoline of Formula LIV, which is then cyclized
to a benzyloxy-1H-imidazo[4,5-c]quinoline of Formula LV. Steps (6)
and (7) of Reaction Scheme XI can be carried out as described for
steps (2) and (3) of Reaction Scheme I.
[0705] In step (8) of Reaction Scheme XI, the Boc group of a
benzyloxy-1H-imidazo[4,5-c]quinoline of Formula LV is hydrolyzed
under acidic conditions to provide a
benzyloxy-1H-imidazo[4,5-c]quinolin-1-amin- e of Formula XLIIa or a
pharmaceutically acceptable salt thereof. The reaction is
conveniently carried out as described in step (4) of Reaction
Scheme I.
[0706] The benzyloxy-1H-imidazo[4,5-c]quinolin-1-amine of Formula
XLIIa is then converted to a
benzyloxy-1H-imidazo[4,5-c]quinolin-1-amine of Formula XLIIIa using
either a two-step procedure as shown in steps (9a) and (10) of
Reaction Scheme XI or a one-step procedure as shown in step (9b).
The two-step procedure, in which a compound of Formula LVI is
isolated, can be carried out as described in steps (5a) and (6) of
Reaction Scheme I. In step (9a), the ketone, aldehyde, or
corresponding ketal or acetal thereof, is selected with R.sub.i and
R.sub.ii groups that will provide the desired R.sub.1a substituent
in a benzyloxy-1H-imidazo[4,57c]quinolin-1-arnine compound of
Formula XLIIIa. Step (9b) of Reaction Scheme XI can be carried out
as described for step (5b) of Reaction Scheme I.
[0707] In steps (11) and (12) of Reaction Scheme XI, a
benzyloxy-1H-imidazo[4,5-c]quinolin-1-amine of Formula XLIIIa is
first oxidized to an N-oxide of Formula LVII, which is then
aminated to provide a
benzyloxy-1H-imidazo[4,5-c]quinoline-1,4-diamine of Formula LVIII,
which is a subgenus of the compounds of the Formulas I and I-1.
Steps (11) and (12) of Reaction Scheme XI can be carried out
according to the procedures described in steps (7) and (8) of
Reaction Scheme I.
[0708] In step (13) of Reaction Scheme XI, the benzyl group of a
benzyloxy-1H-imidazo[4,5-c]quinoline-1,4-diamine of Formula LVIII
is cleaved to provide a
hydroxy-1H-imidazo[4,5-c]quinoline-1,4-diamine of Formula Ih. The
cleavage is conveniently carried out on a Parr apparatus under
hydrogenolysis conditions using a suitable heterogeneous catalyst
such as palladium on carbon in a solvent such as ethanol. The
product or pharmaceutically acceptable salt thereof can be isolated
using conventional methods.
[0709] In step (14) of Reaction Scheme XI a
hydroxy-1H-imidazo[4,5-c]quino- line-1,4-diamine of Formula Ih is
converted to an ether-substituted
1H-imidazo[4,5-c]quinoline-1,4-diamine of Formula I-1c (a subgenus
of compounds of Formulas I and I-1) using a Williamson-type ether
synthesis. The reaction is effected by treating a compound of
Formula Ih with an alkyl halide of Formula Halide-R.sub.4',
Halide-X'--Y'--R.sub.4', Halide-X'--R.sub.4', or
Halide-X'--R.sub.5' in the presence of a base. The reaction is
conveniently carried out by combining the alkyl halide with a
compound of Formula Ih in a solvent such as DMF in the presence of
a suitable base such as cesium carbonate. The reaction can be
carried out at ambient temperature or at an elevated temperature,
for example 65.degree. C. or 85.degree. C. Alternatively, the
reaction can be carried out by treating a solution of a compound of
Formula Ih in a solvent such as DMF with sodium hydride and then
adding the alkyl halide. The product or pharmaceutically acceptable
salt thereof can be isolated using conventional methods.
[0710] Numerous reagents of Formulas Halide-R.sub.4',
Halide-X'--R.sub.4', and Halide-X'--Y'--R.sub.4' are commercially
available, for example, bromo-substituted ketones, esters, and
heterocycles. Other reagents of Formulas Halide-R.sub.4',
Halide-X'--Y'--R.sub.4', or Halide-X'--R.sub.5' can be prepared
using conventional synthetic methods; for example, a
bromo-substituted acid halide of Formula ClC(O)--X'--Br can be
treated with a secondary amine in a suitable solvent such as
dichloromethane to provide a variety of bromo-substituted amides of
Formula
Br--X'--C(O)--N(R.sub.11)--R.sub.4' or 59
[0711] The reaction can be run at a sub-ambient temperature such as
-25.degree. C., and the product or pharmaceutically acceptable salt
thereof can be isolated using conventional methods.
[0712] Reagents of Formula I--X'--NH--C(O)--O--C(CH.sub.3).sub.3
can be prepared in two steps from amino alcohols of Formula
HO--X'--NH.sub.2, many of which are commercially available or
readily prepared by known synthetic methods. An amino alcohol of
Formula HO--X'--NH.sub.2 is first protected with a tert-butoxy
carbonyl group by treating the amino alcohol with di-tert-butyl
dicarbonate in the presence of a base such as aqueous sodium
hydroxide in a suitable solvent such as tetrahydrofuran. The
resulting hydroxyalkylcarbamate of Formula
HO--X'--NH--C(O)--O--C(CH.sub.- 3).sub.3 is then treated with a
solution of iodine, triphenylphosphine, and imidazole at ambient
temperature in a suitable solvent such as dichloromethane. The
product of Formula I--X'--NH--C(O)--O--C(CH.sub.3).s- ub.3 can be
isolated using conventional methods.
[0713] Step (14) of Reaction Scheme XI can alternatively be carried
out by treating a hydroxy-1H-imidazo[4,5-c]quinoline-1,4-diamine of
Formula Ih with an alcohol of Formula HO--X'--Y'--R',
HO--X'--R.sub.5', HO--X'--R.sub.4', or HO--R.sub.4' under Mitsunobu
reaction conditions. Numerous alcohols of these formulas are
commercially available, and others can be prepared using
conventional synthetic methods. The reaction is conveniently
carried out by out by adding triphenylphosphine and an alcohol of
Formula HO--X'--Y'--R.sub.4', HO--X'--R.sub.5', HO--X'--R.sub.4',
or HO--R.sub.4' to a solution of a compound of Formula Ih in a
suitable solvent such as tetrahydrofuran and then slowly adding
diisopropyl azodicarboxylate or diethyl azodicarboxylate. The
reaction can be carried out at ambient temperature or at a
sub-ambient temperature, such as 0.degree. C. The product or
pharmaceutically acceptable salt thereof can be isolated using
conventional methods.
[0714] Compounds of Formula I-1c, wherein R.sub.3b is
--O--X'--NH--C(O)--O--C(CH.sub.3).sub.3, can be prepared by
treating compounds of Formula Ih with alcohols such as tert-butyl
N-(4-hydroxybutyl)carbamate and tert-butyl
N-(5-hydroxypentyi)carbarnate under Mitsunobu conditions or with
alkyl halides of Formula I--X'--NH--C(O)--O--C(CH.sub.3).sub.3 in a
Williamson-type ether synthesis. These compounds of Formula I-1c,
wherein R.sub.3b is --O--X'--NH--C(O)--O--C(CH.sub.3).sub.3, are
then readily converted to other compounds of Formula I-1c using
conventional synthetic methods. For example, compounds in which
R.sub.3b is --O--X'--NH--C(O)--O--C(CH.sub.3)- .sub.3 can be
deprotected and treated according to the methods described in steps
(5) and (6) of Reaction Scheme VII, Parts F and G of Example 14,
and Examples 15 and 23 to provide compounds of Formula I-1c wherein
R.sub.3b is -Z'-X'--Y'--R.sub.4'; Z' is --O--; Y' is --NH-Q-; Q is
--C(R.sub.7)--, --S(O).sub.2--, or --C(R.sub.7)--N(R.sub.11)--; and
X', R.sub.4', R.sub.7, and R.sub.11 are as defined above. Compounds
in which R.sub.3b is a 2-methanesulfonylaminoethoxy group or a
3-methanesulfonylaminopropoxy group are available using these
methods. 6061
[0715] For some embodiments, compounds of Formula I-1c can be
prepared according to Reaction Scheme XII, in which R, R.sub.1a,
R.sub.2a, R.sub.3b, and 1 are as defined above. In step (1) of
Reaction Scheme XII, the benzyl group of a
benzyloxy-1H-imidazo[4,5-c]quinolin-1-amine of Formula XLIIa is
cleaved to provide a hydroxy-1H-imidazo[4,5-c]quinolin-1- -amine of
Formula IXd. In step (2) of Reaction Scheme XII a
hydroxy-1H-imidazo[4,5-c]quinolin-1-amine of Formula IXd is
converted to an ether-substituted 1H-imidazo[4,5-c]quinolin-1-amine
of Formula LIX. In steps (3) and (4) of Reaction Scheme XII, an
ether-substituted 1H-imidazo[4,5-c]quinolin-1-amine of Formula LIX
is first oxidized to an N-oxide of Formula LX, which is then
aminated to provide an ether-substituted
1H-imidazo[4,5-c]quinoline-1,4-diamine of Formula I-1c, which is a
subgenus of the compounds of Formula I-1. Steps (1), (2), (3), and
(4) of Reaction Scheme XII can be carried out as described in steps
(13), (14), (11), and (12), respectively, of Reaction Scheme XI.
62
[0716] Pharmaceutical Compositions and Biological Activity
[0717] Pharmaceutical compositions of the invention contain a
therapeutically effective amount of a compound of the invention as
described above in combination with a pharmaceutically acceptable
carrier.
[0718] The term "a therapeutically effective amount" or "effective
amount" means an amount of the compound sufficient to induce a
therapeutic or prophylactic effect, such as cytokine induction,
immunomodulation, antitumor activity, and/or antiviral activity.
Although the exact amount of active compound used in a
pharmaceutical composition of the invention will vary according to
factors known to those of skill in the art, such as the physical
and chemical nature of the compound, the nature of the carrier, and
the intended dosing regimen, it is anticipated that the
compositions of the invention will contain sufficient active
ingredient to provide a dose of about 100 ng/kg to about 50 mg/kg,
preferably about 10 .mu.g/kg to about 5 mg/kg, of the compound to
the subject. A variety of dosage forms may be used, such as
tablets, lozenges, capsules, parenteral formulations, syrups,
creams, ointments, aerosol formulations, transdermal patches,
transmucosal patches and the like.
[0719] The compounds of the invention can be administered as the
single therapeutic agent in the treatment regimen, or the compounds
of the invention may be administered in combination with one
another or with other active agents, including additional immune
response modifiers, antivirals, antibiotics, antibodies, proteins,
peptides, oligonucleotides, etc.
[0720] Compounds of the invention have been shown to modulate
(e.g., induce) the production of certain cytokines in experiments
performed according to the tests set forth below. These results
indicate that the compounds are useful as immune response modifiers
that can modulate the immune response in a number of different
ways, rendering them useful in the treatment of a variety of
disorders.
[0721] Cytokines whose production may be induced by the
administration of compounds according to the invention generally
include interferon-.alpha. (IFN-.alpha.) and/or tumor necrosis
factor-.alpha. (TNF-.alpha.) as well as certain interleukins (IL).
Cytokines whose biosynthesis may be induced by compounds of the
invention include IFN-.alpha., TNF-.alpha.; IL-1, IL-6, IL-10 and
IL-12, and a variety of other cytokines. Among other effects, these
and other cytokines can inhibit virus production and tumor cell
growth, making the compounds useful in the treatment of viral
diseases and neoplastic diseases. Accordingly, the invention
provides a method of inducing cytokine biosynthesis in an animal
comprising administering an effective amount of a compound or
composition of the invention to the animal. The animal to which the
compound or composition is administered for induction of cytokine
biosynthesis may have a disease as described infra, for example a
viral disease or a neoplastic disease, and administration of the
compound may provide therapeutic treatment. Alternatively, the
compound may be administered to the animal prior to the animal
acquiring the disease so that administration of the compound may
provide a prophylactic treatment.
[0722] In addition to the ability to induce the production of
cytokines, compounds of the invention may affect other aspects of
the innate immune response. For example, natural killer cell
activity may be stimulated, an effect that may be due to cytokine
induction. Certain compounds may also activate macrophages, which
in turn stimulate secretion of nitric oxide and the production of
additional cytokines. Further, certain compounds may cause
proliferation and differentiation of B-lymphocytes.
[0723] Compounds of the invention also have an effect on the
acquired immune response. For example, the production of the T
helper type 1 (T.sub.H1) cytokine IFN-.gamma. is induced indirectly
and the production of the T helper type 2 (T.sub.H2) cytokines
IL-4, IL-5 and IL-13 are inhibited upon administration of certain
compounds.
[0724] Whether for prophylaxis or therapeutic treatment of a
disease, and whether for effecting innate or acquired immunity, the
compound or composition may be administered alone or in combination
with one or more active components as in, for example, a vaccine
adjuvant. When administered with other components, the compound and
other component or components may be administered separately;
together but independently such as in a solution; or together and
associated with one another such as (a) covalently linked or (b)
non-covalently associated, e.g., in a colloidal suspension.
[0725] Conditions for which IRMs identified herein may be used as
treatments include, but are not limited to:
[0726] (a) viral diseases such as, for example, diseases resulting
from infection by an adenovirus, a herpesvirus (e.g., HSV-I,
HSV-II, CMV, or VZV), a poxvirus (e.g., an orthopoxvirus such as
variola or vaccinia, or molluscum contagiosum), a picomavirus
(e.g., rhinovirus or enterovirus), an orthomyxovirus (e.g.,
influenzavirus), a paramyxovirus (e.g., parainfluenzavirus, mumps
virus, measles virus, and respiratory syncytial virus (RSV)), a
coronavirus (e.g., SARS), a papovavirus (e.g., papillomaviruses,
such as those that cause genital warts, common warts, or plantar
warts), a hepadnavirus (e.g., hepatitis B virus), a flavivirus
(e.g., hepatitis C virus or Dengue virus), or a retrovirus (e.g., a
lentivirus such as HIV);
[0727] (b) bacterial diseases such as, for example, diseases
resulting from infection by bacteria of, for example, the genus
Escherichia, Enterobacter, Salmonella, Staphylococcus, Shigella,
Listeria, Aerobacter, Helicobacter, Klebsiella, Proteus,
Pseudomonas, Streptococcus, Chlamydia, Mycoplasma, Pneumococcus,
Neisseria, Clostridium, Bacillus, Corynebacterium, Mycobacterium,
Campylobacter, Vibrio, Serratia, Providencia, Chromobacterium,
Brucella, Yersinia, Haemophilus, or Bordetella;
[0728] (c) other infectious diseases, such chlamydia, fungal
diseases including but not limited to candidiasis, aspergillosis,
histoplasmosis, cryptococcal meningitis, or parasitic diseases
including but not limited to malaria, pneumocystis carnii
pneumonia, leishmaniasis, cryptosporidiosis, toxoplasmosis, and
trypanosome infection; and
[0729] (d) neoplastic diseases, such as intraepithelial neoplasias,
cervical dysplasia, actinic keratosis, basal cell carcinoma,
squamous cell carcinoma, renal cell carcinoma, Kaposi's sarcoma,
melanoma, renal cell carcinoma, leukemias including but not limited
to myelogeous leukemia, chronic lymphocytic leukemia, multiple
myeloma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, B-cell
lymphoma, and hairy cell leukemia, and other cancers; and
[0730] (e) T.sub.H2-mediated, atopic, and autoimmune diseases, such
as atopic dermatitis or eczema, eosinophilia, asthma, allergy,
allergic rhinitis, systemic lupus erythematosus, essential
thrombocythaemia, multiple sclerosis, Ommen's syndrome, discoid
lupus, alopecia areata, inhibition of keloid formation and other
types of scarring, and enhancing would healing, including chronic
wounds.
[0731] IRMs identified herein also may be useful as a vaccine
adjuvant for use in conjunction with any material that raises
either humoral and/or cell mediated immune response, such as, for
example, live viral, bacterial, or parasitic immunogens;
inactivated viral, tumor-derived, protozoal, organism-derived,
fungal, or bacterial immunogens, toxoids, toxins; self-antigens;
polysaccharides; proteins; glycoproteins; peptides; cellular
vaccines; DNA vaccines; recombinant proteins; glycoproteins;
peptides; and the like, for use in connection with, for example,
BCG, cholera, plague, typhoid, hepatitis A, hepatitis B, hepatitis
C, influenza A, influenza B, parainfluenza, polio, rabies, measles,
mumps, rubella, yellow fever, tetanus, diphtheria, hemophilus
influenza b, tuberculosis, meningococcal and pneumococcal vaccines,
adenovirus, HIV, chicken pox, cytomegalovirus, dengue, feline
leukemia, fowl plague, HSV-1 and HSV-2, hog cholera, Japanese
encephalitis, respiratory syncytial virus, rotavirus, papilloma
virus, yellow fever, and Alzheimer's Disease.
[0732] IRMs may also be particularly helpful in individuals having
compromised immune function. For example, IRM compounds may be used
for treating the opportunistic infections and tumors that occur
after suppression of cell mediated immunity in, for example,
transplant patients, cancer patients and HIV patients.
[0733] Thus, one or more of the above diseases or types of
diseases, for example, a viral disease or a neoplastic disease may
be treated in an animal in need thereof (having the disease) by
administering a therapeutically effective amount of a compound or
salt of Formula I, I-1, I-2, I-3, II, or II-1 to the animal.
[0734] An amount of a compound effective to induce cytokine
biosynthesis is an amount sufficient to cause one or more cell
types, such as monocytes, macrophages, dendritic cells and B-cells
to produce an amount of one or more cytokines such as, for example,
IFN-.alpha., TNF-.alpha., IL-1, IL-6, IL-10 and IL-12 that is
increased over the background level of such cytokines. The precise
amount will vary according to factors known in the art but is
expected to be a dose of about 100 ng/kg to about 50 mg/kg,
preferably about 10 .mu.g/kg to about 5 mg/kg. The invention also
provides a method of treating a viral infection in an animal and a
method of treating a neoplastic disease in an animal comprising
administering an effective amount of a compound or composition of
the invention to the animal. An amount effective to treat or
inhibit a viral infection is an amount that will cause a reduction
in one or more of the manifestations of viral infection, such as
viral lesions, viral load, rate of virus production, and mortality
as compared to untreated control animals. The precise amount that
is effective for such treatment will vary according to factors
known in the art but is expected to be a dose of about 100 ng/kg to
about 50 mg/kg, preferably about 10 .mu.g/kg to about 5 mg/kg. An
amount of a compound effective to treat a neoplastic condition is
an amount that will cause a reduction in tumor size or in the
number of tumor foci. Again, the precise amount will vary according
to factors known in the art but is expected to be a dose of about
100 ng/kg to about 50 mg/kg, preferably about 10 .mu.g/kg to about
5 mg/kg.
EXAMPLES
[0735] Objects and advantages of this invention are further
illustrated by the following examples, but the particular materials
and amounts thereof recited in these examples, as well as other
conditions and details, should not be construed to unduly limit
this invention.
Example 1
2-Butyl-N.sup.1-isopropyl-1H-imidazo[4,5-c]quinoline-1,4-diamine
[0736] 63
[0737] Part A
[0738] A solution of 4-chloro-3-nitroquinoline (5.00 g, 24.0 mmol)
in 120 ML of anhydrous CH.sub.2Cl.sub.2 was treated with
triethylamine (6.7 mL, 48.2 mmol) and tert-butyl carbazate (3.20 g,
24.2 mmol). After stirring under nitrogen for 2.5 hour (h), an
additional portion of tert-butyl carbazate (3.2 g, 24.2 mmol) was
added. After stirring overnight, the deep red solution was washed
with H.sub.2O (2.times.) and brine. The organic portion was dried
over Na.sub.2SO.sub.4 and concentrated to give a red foam. The
material was passed through a SiO.sub.2 column eluting with 2.5%
methanol/CH.sub.2Cl.sub.2. The resulting red powder was treated
with 5:1 hexanes/CH.sub.2Cl.sub.2 and filtered. The solid was
washed several times with hexanes and was dried under vacuum to
give tert-butyl N'-(3-nitroquinolin-4-yl)hydrazinecarboxylate (4.97
g) as an orange powder.
[0739] Part B
[0740] A suspension of tert-butyl
N'-(3-nitroquinolin-4-yl)hydrazinecarbox- ylate (2.50 g, 8.22 mmol)
in 150 mL of isopropanol was treated with 1.0 g of 10% palladium on
carbon and the mixture was shaken under an atmosphere of hydrogen
(3.8.times.10.sup.5 Pa) for 2 h. The reaction mixture was then
filtered through a pad of CELITE filter agent and rinsed with
isopropanol, and the filtrate was concentrated under reduced
pressure to give N'-(3-aminoquinolin-4-yl)hydrazine tert-butyl
carboxylate (2.18 g) as a yellow solid.
[0741] Part C
[0742] A solution of N'-(3-aminoquinolin-4-yl)hydrazine tert-butyl
carboxylate (2.18 g, 7.96 mmol) in 80 mL of anhydrous
CH.sub.2Cl.sub.2 was cooled to 0.degree. C. and treated with
triethylamine (1.12 mL, 8.00 mmol) and valeryl chloride (0.95 mL,
8.00 mmol) under an atmosphere of nitrogen. After stirring for 3 h,
the reaction mixture was concentrated under reduced pressure and
the residue was treated with Et.sub.2O and filtered. The filtrate
was concentrated and the resulting black tar was dissolved in 80 ML
of ethanol and treated with 3 mL of triethylamine and the mixture
was refluxed overnight. The reaction mixture was concentrated under
reduced pressure. Chromatography (SiO.sub.2, 1-5% methanol
(MeOH)/CHCl.sub.3) gave tert-butyl
N-(2-butyl-1H-imidazo[4,5-c]quinolin-1- -yl)carbamate (1.41 g) as a
mauve foam.
[0743] Part D
[0744] tert-Butyl
N-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)carbamate (830 mg, 2.44
mmol) was dissolved in 20 mL of 1.5 M HCl in ethanol (EtOH) and the
reaction mixture was heated to reflux for 1.5 h. The reaction
mixture was cooled and concentrated under reduced pressure to give
a brown solid. The material was dissolved in 50 mL of hot
isopropanol and the solution was allowed to cool overnight. The
resulting crystals were isolated by filtration. A second crop was
obtained from the filtrate by crystallization from
isopropanol/Et.sub.2O. The total yield of
2-butyl-1H-imidazo[4,5-c]quinolin-1-amine hydrochloride was 570 mg.
mp>250.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
9.68 (s, 1H), 9.35 (d, J=8.3 Hz, 1H), 8.47 (d, J=8.0 Hz, 1H), 8.03
(t, J=7.1 Hz, 1H), 7.98 (t, J=Hz, 1H), 6.85 (s, 2H), 3.13 (t, J=7.6
Hz, 2H), 1.89, (m, 2H), 1.49 (m, 2H), 0.98 (t, J=7.3 Hz, 3H);
.sup.13C NMR (75 MHz, DMSO-d.sub.6) .delta. 163.5, 139.4, 136.1,
134.0, 131.8, 130.4, 128.9, 122.6, 120.2, 115.6, 28.2, 25.7, 22.1,
13.3; Anal. Calcd for C.sub.14H.sub.16N.sub.4HCl: C, 60.76; H,
6.19; N, 20.24; Cl, 12.81. Found: C, 60.78; H, 6.19; N, 20.21; Cl,
12.78.
[0745] Part E
[0746] A solution of 2-butyl-1H-imidazo[4,5-c]quinolin-1-amine
hydrochloride (520 mg, 2.17 mmol) in 10 mL of isopropanol was
treated with 2 mL of acetone and 200 mg of DOWEX W50-X1 acid resin.
The reaction mixture was heated to 55.degree. C. overnight. The
reaction mixture was treated with an additional 10 mL of
isopropanol and 5 mL of acetone and heated to 70.degree. C. for 2
h. The reaction mixture was filtered and the filtrate was treated
with 0.5 mL of triethylamine and concentrated under reduced
pressure. Chromatography (SiO.sub.2, 3% MeOH/CHCl.sub.3) gave
N-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)isopropylideneamine (421
mg) as a brown oil.
[0747] Part F
[0748] A solution of
N-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)isopropylid- eneamine
(406 mg, 1.45 mmol) in 15 mL of MeOH was treated with NaBH.sub.4
(500 mg, 13.2 mmol). After stirring for 2 days (d), the reaction
was quenched with saturated NaHCO.sub.3 solution and extracted into
ethyl acetate (EtOAc). The organic portion was washed with H.sub.2O
and brine and dried over Na.sub.2SO.sub.4. Chromatography
(SiO.sub.2, EtOAc) gave
N-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)isopropylamine (372 mg)
as a mauve solid.
[0749] Part G
[0750] A solution of
N-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)isopropylaa- mine (334
mg, 1.18 mmol) in 10 mL of CH.sub.2Cl.sub.2 was treated with
3-chloroperoxybenzoic acid (MCPBA) (77% max., 334 mg, 1.45 mmol).
After stirring for 3 h, the reaction was quenched with saturated
NaHCO.sub.3 solution and extracted into CH.sub.2Cl.sub.2. The
organic portion was washed with saturated NaHCO.sub.3 solution,
H.sub.2O and brine. The organic portion was dried over
Na.sub.2SO.sub.4, filtered and concentrated to give
N-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)is- opropylamine
(338 mg) as a light brown solid.
[0751] Part H
[0752] A solution of
N-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)iso- propylamine
(332 mg, 1.11 mmol) in 15 mL of 1,2-dichloroethane was placed in a
pressure vessel and heated to 70.degree. C. The rapidly stirred
solution was then treated with 3 mL of concentrated NH.sub.4OH
solution and p-toluenesulfonyl chloride (233 mg, 1.22 mmol), the
reaction vessel was capped, and heating was continued for 2 h. The
reaction mixture was then cooled to ambient temperature and treated
with 50 mL of CH.sub.2Cl.sub.2. The reaction mixture was washed
with H.sub.2O, 1% Na.sub.2CO.sub.3 solution (3.times.), H.sub.2O
and brine. The organic portion was dried over Na.sub.2SO.sub.4,
filtered and concentrated. Chromatography (SiO.sub.2, 5-10%
MeOH/CHCl.sub.3) gave 320 mg of a light brown solid.
Crystallization from CH.sub.2Cl.sub.2/hexanes gave
2-butyl-N.sup.1-isopropyl-1H-imidazo[4,5-c]quinoline-1,4-diamine
(230 mg) as colorless crystals. mp 157.1-158.7.degree. C. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 8.40 (m, 1H), 7.80 (m, 1H),
7.50 (m, 1H), 7.31 (m, 1H), 5.41 (s, 2H), 4.95 (s, 1H), 3.68 (m,
1H), 2.96 (t, J=7.6 Hz, 2H), 1.93-1.82 (m, 2H), 1.48 (m, 2H), 1.16
d, J=6.4 Hz, 6H), 1.00 (t, J=7.3 Hz, 3H); .sup.13C NMR (75 MHz,
DMSO-d.sub.6).delta. 155.1, 151.8, 144.7, 133.1, 127.3, 126.6,
124.7, 122.0, 120.4, 115.3, 52.1, 30.3, 26.8, 23.0, 20.8, 14.2; MS
m/z 298 (M+H).sup.+; Anal. Calcd for C.sub.17H.sub.23N.sub.5: C,
68.66; H, 7.80; N, 23.55. Found: C, 68.30; H, 7.68; N, 23.33.
Example 2
N.sup.1-Benzyl-2-butyl-1H-imidazo[4,5-c]quinoline-1,4-diamine
[0753] 64
[0754] Part A
[0755] A solution of 2-butyl-1H-imidazo[4,5-c]quinolin-1-amine
hydrochloride (503 mg, 1.82 mmol) in 10 mL of isopropanol was
treated with benzaldehyde (220 .mu.L, 2.17 mmol) and 200 mg of
DOWEX W50-X1 acid resin. The reaction mixture was heated to reflux
overnight. The reaction mixture was filtered, and the filtrate was
treated with 0.5 mL of triethylamine and concentrated under reduced
pressure. The resulting oil was dissolved in 75 mL of
CH.sub.2Cl.sub.2 and washed with saturated NaHCO.sub.3 solution,
H.sub.2O and brine. The organic was dried over Na.sub.2SO.sub.4,
filtered and concentrated to give
N-benzylidene(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)amine (575 mg)
as a light yellow solid.
[0756] Part B
[0757] A solution of
N-benzylidene(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)- amine (575
mg, 1.75 mmol) in 40 mL of MeOH was treated with NaBH.sub.4 (250
mg, 6.58 mmol). After stirring for 4 h, the reaction was quenched
with saturated NaHCO.sub.3 solution and extracted into CHCl.sub.3.
The organic portion was washed with H.sub.2O and brine and dried
over Na.sub.2SO.sub.4. Chromatography (SiO.sub.2, 50-67%
EtOAc/hexanes) gave
N-benzyl(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)amine (427 mg) as a
yellow solid.
[0758] Part C
[0759] A solution of
N-benzyl(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)amine (427 mg, 1.29
mmol) in 20 mL of CH.sub.2Cl.sub.2 was treated with MCPBA (77%
max., 325 mg, 1.41 mmol). After stirring for 3 h, the reaction was
quenched with saturated NaHCO.sub.3 solution and extracted into
CH.sub.2Cl.sub.2. The organic portion was washed with saturated
NaHCO.sub.3 solution, H.sub.2O and brine. The organic was dried
over Na.sub.2SO.sub.4, filtered and concentrated to give
N-benzyl(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)amine (393
mg) as a light brown foam.
[0760] Part D
[0761] A solution of
N-benzyl(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-- yl)amine
(393 mg, 1.14 mmol) in 20 mL of 1,2-dichloroethane was placed in a
pressure vessel and heated to 70.degree. C. The rapidly stirred
solution was then treated with 5 mL of concentrated NH.sub.4OH
solution andp-toluenesulfonyl chloride (239 mg, 1.25 mmol), the
reaction vessel was capped, and heating was continued for 2 h. The
reaction mixture was then cooled to ambient temperature and treated
with 50 mL of CH.sub.2Cl.sub.2. The reaction mixture was washed
with H.sub.2O, 1% Na.sub.2CO.sub.3 solution (3.times.), H.sub.2O
and brine. The organic portion was dried over Na.sub.2SO.sub.4,
filtered and concentrated. Chromatography (SiO.sub.2, 5%
MeOH/CHCl.sub.3) followed by crystallization from propyl
acetate/hexanes gave N.sup.1-benzyl-2-butyl-1-
H-imidazo[4,5-c]quinoline-1,4-diamine (237 mg) as light-yellow
crystals. mp 159.3-160.5.degree. C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 8.31 (d, J=8.2 Hz, 1H), 7.83 (d, J=8.4 Hz,
1H), 7.54 (m, 1H), 7.42-7.31 (m, 6H), 5.44 (s, 2H), 5.26 (t, J=5.6
Hz, 1H), 4.37 (d, J=5.6 Hz, 2H), 2.71 (t, J=8.4 Hz, 2H), 1.74 (m,
2H), 1.42 (m, 2H), 0.95 (t, J=7.3 Hz, 3H); MS m/z 346 (M+H).sup.+;
Anal. Calcd for C.sub.21H.sub.23N.sub.5: C, 73.02; H, 6.71; N,
20.27. Found: C, 72.75; H, 6.55; N, 20.46.
Example 3
N.sup.1-Isopropyl-2-methyl-1H-imidazo[4,5-c]quinoline-1,4-diamine
[0762] 65
[0763] Part A
[0764] A solution of N'-(3-aminoquinolin-4-yl)hydrazine tert-butyl
carboxylate (11.67 g, 42.5 mmol) in 400 mL of anhydrous toluene was
treated with trimethyl orthoacetate (5.96 mL, 46.8 mmol) and
pyridine hydrochloride (100 mg) under an atmosphere of N.sub.2 and
heated to reflux. After stirring for 3 h, the reaction mixture was
concentrated under reduced pressure to give a red solid.
Chromatography (SiO.sub.2, 0-10% MeOH/EtOAc) gave tert-butyl
N-(2-methyl-1H-imidazo[4,5-c]quinolin-1- -yl)carbamate (10.7 g) as
a yellow foam.
[0765] Part B
[0766] tert-Butyl
N-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)carbamate (5.00 g, 16.8
mmol) was dissolved in 40 mL of 1.65 M HCl in EtOH, and the
reaction mixture was heated to reflux for 2 h. The reaction mixture
was cooled and concentrated under reduced pressure to give a brown
solid. The brown solid was crystallized from ethanol/H.sub.2O to
give 3.13 g of 2-methyl-1H-imidazo[4,5-c]quinolin-1-amine
hydrochloride.
[0767] Part C
[0768] A suspension of 2-methyl-1H-imidazo[4,5-c]quinolin-1-amine
hydrochloride (1.79 g, 7.62 mmol) in 30 mL of 2,2-dimethoxypropane
was treated with 90 mg of p-toluenesulfonic acid. The reaction
mixture was heated to 100.degree. C. overnight. The reaction
mixture was then treated with 10 mL of H.sub.2O and 10 mL of MeOH,
and heating was continued for 24 h. The reaction mixture was cooled
and concentrated under reduced pressure. The resulting oil was
dissolved in 50 mL of CHCl.sub.3 and washed with 2%
Na.sub.2CO.sub.3 solution, H.sub.2O and brine. The organic portion
was dried over Na.sub.2SO.sub.4, filtered and concentrated to give
N-isopropylidene(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)amine
(1.82 g) as a yellow solid.
[0769] Part D
[0770] A solution of
N-isopropylidene(2-methyl-1H-imidazo[4,5-c]quinolin-1- -yl)amine
(1.82 g, 7.64 mmol) dissolved in 40 mL of MeOH was treated with
NaBH4 (1.16 g, 30.6 mmol). After stirring for 18 h, the reaction
was quenched with saturated NH.sub.4Cl solution and partitioned
between CH.sub.2Cl.sub.2 and 2% Na.sub.2CO.sub.3 solution. The
organic portion was washed with 2% Na.sub.2CO.sub.3 solution,
H.sub.2O and brine and dried over Na.sub.2SO.sub.4. The resulting
organic portion was filtered and concentrated under reduced
pressure to give N-isopropyl(2-methyl-1H-i-
midazo[4,5-c]quinolin-1-yl)amine (1.84 g) as a yellow foam.
[0771] Part E
[0772] A solution of
N-isopropyl(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)a- amine (1.84
g, 7.66 inmol) dissolved in 50 mL of 1,2-dichloroethane was treated
with MCPBA (77% max., 2.36 g, 9.58 mmol). After stirring for 3 h,
the reaction mixture was treated with 2% Na.sub.2CO.sub.3 solution
and extracted into CH.sub.2Cl.sub.2. The organic portion was washed
with saturated 2% Na.sub.2CO.sub.3 solution, H.sub.2O and brine.
The organic portion was dried over Na.sub.2SO.sub.4, filtered and
concentrated to give
N-isopropyl(2-methyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)amine
(1.95 g) as a light orange solid.
[0773] Part F
[0774] A solution of
N-isopropyl(2-methyl-5-oxido-1H-imidazo[4,5-c]quinoli- n-1-yl)amine
(1.95 g, 7.61 mmol) in 75 mL of CH.sub.2Cl.sub.2 was treated with
35 mL of concentrated NH.sub.4OH solution. To the rapidly stirred
solution was added p-toluenesulfonyl chloride (1.52 g, 7.99 mmol).
After stirring for 30 min, the reaction mixture was treated with
CHCl.sub.3 (25 mL) and H.sub.2O (35 mL). The layers were separated
and the organic portion was washed with 2% Na.sub.2CO.sub.3
solution (2.times.), H.sub.2O and brine. The organic portion was
dried over Na.sub.2SO.sub.4, filtered and concentrated to give a
light-yellow solid. Crystallization from propyl acetate gave
NM-isopropyl-2-methyl-]H-imidazo[4,5-c]quinoline-1,4-- diamine (747
mg) as off-white crystals. mp 227-229.degree. C.; .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.19 (dd, J=8.2, 1.1 Hz, 1 H), 7.79 (dd,
J=8.4, 0.7 Hz, 1 H), 7.53-7.45 (m, 1 H), 7.33-7.26 (m, 1 H), 5.42
(s, 2 H), 4.91 (d, J=1.4 Hz, 1 H), 3.73-3.62 (m, 1 H), 2.64 (s, 3
H), 1.15 (d, J=6.2 Hz, 6 H); .sup.13C NMR (75 MHz, CDCl.sub.3)
.delta. 151.4, 151.3, 144.9, 133.3, 127.6, 127.3, 124.6, 122.4,
120.2, 115.4, 52.3, 20.9, 13.8; MS m/z 256 (M+H).sup.+; Anal. Calcd
for C.sub.14H.sub.17N.sub.5: C, 65.86; H, 6.71; N, 27.43; Found: C,
65.59; H, 6.56; N, 27.09.
Example 4
N.sup.1-Benzyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1,4-diamine
[0775] 66
[0776] Part A
[0777] A solution of N'-(3-aminoquinolin-4-yl)hydrazine tert-butyl
carboxylate (12.15 g, 44.3 mmol) in 200 mL of anhydrous
CH.sub.2Cl.sub.2 was cooled to 0.degree. C. and treated with
triethylamine (7.72 mL, 55.4 mmol) and 2-ethoxyacetyl chloride
(5.70 g, 46.5 mmol) under an atmosphere of N.sub.2. After 3 h, an
additional 1 mL of 2-ethoxyacetyl chloride was added. After
stirring for 2 h, the reaction mixture was concentrated under
reduced pressure to give a brown solid. This was dissolved in 150
mL of EtOH and treated with 18.5 mL of triethylamine, and the
mixture was refluxed overnight. The reaction mixture was
concentrated under reduced pressure to give a dark-red oil. The red
oil was dissolved in 200 mL of CH.sub.2Cl.sub.2 and washed with
H.sub.2O (2.times.75 mL) and brine (75 mL). The organic portion was
dried over Na.sub.2SO.sub.4, filtered, and concentrated under
reduced pressure to give a red solid. The solid was treated with a
minimum amount of hot Et.sub.2O and filtered to remove insoluble
material. The filtrate was concentrated to give tert-butyl
N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)carbamate (14.3 g)
as a tan solid.
[0778] Part B
[0779] tert-Butyl
N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)carbama- te (14.3
g, 41.8 mmol) was dissolved in 150 mL of 2 M HCl in EtOH, and the
reaction mixture was heated to reflux for 3 h. The reaction mixture
was cooled and concentrated under reduced pressure to give a brown
solid. The brown solid was dissolved in 100 mL of H.sub.2O and
treated with 100 mL of concentrated NH.sub.4OH solution. The basic,
aqueous solution was then extracted with CH.sub.2Cl.sub.2
(4.times.). The combined organic layers were then washed with brine
and dried over Na.sub.2SO.sub.4. The solution was filtered and
concentrated under reduced pressure to give a brown foam. The foam
was triturated with Et.sub.2O (150 mL) and filtered. The filtrate
was concentrated to give 2-ethoxymethy-1H-imidazo[4,5-c]quinolin-
-1-amine (5.77 g) as a tan solid.
[0780] Part C
[0781] A solution of
2-ethoxymethy-1H-imidazo[4,5-c]quinolin-1-amine (1.50 g, 6.19 mmol)
in 50 mL of isopropanol was treated with benzaldehyde (0.66 mL,
6.50 mmol) and 10 mg of p-toluenesulfonic acid. The reaction
mixture was heated to 120.degree. C. for 3 d. The reaction mixture
was cooled, and a precipitate started to form. The reaction mixture
was treated with Et.sub.2O and then filtered to give
N-benzylidene-(2-ethoxymethy-1H-imida- zo[4,5-c]quinolin-1-yl)amine
(1.21 g) as a gray solid.
[0782] Part D
[0783] A solution of
N-benzylidene-(2-ethoxymethy-1H-imidazo[4,5-c]quinoli- n 1-yl)amine
(1.00 g, 3.03 mmol) in 50 mL of MeOH was treated with NaBH.sub.4
(458 mg, 12.1 mmol). After stirring for 1.5 h, the reaction mixture
was concentrated, then treated with saturated NaHCO.sub.3 solution,
and extracted into CHCl.sub.3. The organic portion was washed with
H.sub.2O and brine and dried over Na.sub.2SO.sub.4. The resulting
solution was filtered and concentrated to give
N-benzyl-(2-ethoxyrnethy-1- H-imidazo[4,5-c]quinolin-1-yl)amine
(1.01 g) as a tan solid.
[0784] Part E
[0785] A solution of
N-benzyl-(2-ethoxymethy-1H-imidazo[4,5-c]quinolin-1-y- l)amine
(1.01 g, 3.04 mmol) in 50 mL of CH.sub.2Cl.sub.2 was treated with
MCPBA (77% max., 1.02 g, 4.56 mmol). After stirring for 3 h, the
reaction mixture was quenched with 2% Na.sub.2CO.sub.3 solution and
extracted into CH.sub.2Cl.sub.2. The organic portion was washed
with H.sub.2O and brine. The organic portion was dried over
Na.sub.2SO.sub.4, filtered and concentrated to give
N-benzyl-(2-ethoxymethy-5-oxido-1H-imidazo[4,5-c]qui-
nolin-1-yl)amine (0.99 g) as a light-yellow solid.
[0786] Part F
[0787] A solution of
N-benzyl-(2-ethoxymethy-5-oxido-1H-imidazo[4,5-c]quin-
olin-1-yl)amine (0.99 g, 2.84 mmol) in 50 mL of CH.sub.2Cl.sub.2
was treated with 25 mL of concentrated NH.sub.4OH solution. To the
rapidly stirred solution was added p-toluenesulfonyl chloride (569
mg, 2.98 mmol). After stirring for 30 min, the reaction was treated
with CH.sub.2Cl.sub.2 (50 mL) and H.sub.2O (25 mL). The layers were
separated and the organic portion was washed 2% Na.sub.2CO.sub.3
solution, H.sub.2O and brine. The organic portion was dried over
Na.sub.2SO.sub.4, filtered and concentrated to give a tan solid.
Chromatography (SiO.sub.2, 2% MeOH/CHCl.sub.3 containing 0.5%
concentrated NH.sub.4OH) followed by crystallization from propyl
acetate gave N.sup.1-benzyl-2-ethoxymethyl-1H-
-imidazo[4,5-c]quinoline-1,4-diamine (148 mg) as white needles. mp
152-155.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
8.61 (dd, J=8.2, 1.2 Hz, 1 H), 7.85-7.77 (mn, 1H), 7.59-7.52 (m,
1H), 7.42-7.34 (m, 4 H), 7.33-7.24 (m, 2 H), 6.02 (t, J=6.6 Hz,
1H), 5.39 (s, 2 H), 4.43 (s, 2 H), 4.40 (d, J=6.7 Hz, 2 H), 3.55
(q, J=7.0 Hz, 2 H), 1.22 (t, J=7.0 Hz, 3 H); .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 151.1, 147.9, 144.9, 135.7, 129.2, 129.1,
128.6, 127.8, 126.7, 122.4, 120.7, 66.7, 65.3, 56.7, 15.0; MS m/z
348 (M+H).sup.+; Anal. Calcd for C.sub.20H.sub.21N.sub.5O.mu-
ltidot.0.36H.sub.2O: C, 68.90; H, 6.11; N, 20.09; Found: C, 68.50;
H, 6.07; N, 20.11.
Example 5
2-Ethoxymethyl-N.sup.1-isopropyl-1H-imidazo[4,5-c]quinoline-1,4-diamine
[0788] 67
[0789] Part A
[0790] A solution of
2-ethoxymethy-1H-imidazo[4,5-c]quinolin-1-amine (2.50 g, 10.3 mmol)
in 250 mL of 1,2-dichloroethane was treated with acetone (0.83 mL,
11.3 mmol), acetic acid (0.65 mL, 11.3 mmol) and sodium
triacetoxyborohydride (2.39 g, 11.3 mL). After stirring overnight,
additional acetone (5 mL), acetic acid (0.65 mL, 11.3 mmol) and
sodium triacetoxyborohydride (2.39 g, 11.3 mL) were added. After 2
d, the reaction was carefully quenched by addition of saturated
NaHCO.sub.3 solution. The layers were separated and the aqueous
portion was extracted with additional CH.sub.2Cl.sub.2. The
combined organic layers were washed with H.sub.2O and brine, dried
over Na.sub.2SO.sub.4, and concentrated under reduced pressure to
give a brown oil. Some isopropylidene intermediate was still
present, so the material was dissolved in 50 mL of MeOH and treated
with NaBH.sub.4 (1.0 g). After 2 h, the reaction was quenched by
the addition of H.sub.2O and the reaction mixture was concentrated
under reduced pressure. The residue was partitioned between
saturated NaHCO.sub.3 solution and CH.sub.2Cl.sub.2. The layers
were separated and the organic portion was washed with saturated
NaHCO.sub.3, H.sub.2O and brine. The organic portion was dried over
Na.sub.2SO.sub.4, filtered, and concentrated under reduced
pressure. Chromatography (SiO.sub.2, 4% MeOH/CHCl.sub.3) gave
N-(2-ethoxymethy-1H-imidazo[4,5-c]qu- inolin-1-yl)isopropylamine
(0.98 g) as a brown oil.
[0791] Part B
[0792] A solution of
N-(2-ethoxymethy-1H-imidazo[4,5-c]quinolin-1-yl)isopr- opylamine
(0.98 g, 3.45 mmol) in 35 mL of CH.sub.2Cl.sub.2 was treated with
MCPBA (77% max., 1.10 g, 4.48 mmol). After stirring for 3 h, the
reaction was quenched with 2% Na.sub.2CO.sub.3 solution and
extracted into CH.sub.2Cl.sub.2. The organic portion was washed
with H.sub.2O and brine. The organic portion was dried over
Na.sub.2SO.sub.4, filtered and concentrated to give
N-(2-ethoxymethy-5-oxido-1H-imidazo[4,5-c]quinolin-1-
-yl)isopropylamine (0.93 g) as a light-orange solid.
[0793] Part C
[0794] A solution of
N-(2-ethoxymethy-5-oxido-1H-imidazo[4,5-c]quinolin-1--
yl)isopropylamine (0.93 g, 3.10 mmol) in 25 mL of CH.sub.2Cl.sub.2
was treated with 15 mL of concentrated NH.sub.4OH solution. To the
rapidly stirred solution was added p-toluenesulfonyl chloride (620
mg, 3.25 mmol). After stirring for 30 min, the reaction was treated
with CH.sub.2Cl.sub.2 (20 mL) and H.sub.2O (15 mL). The layers were
separated and the organic portion was washed with 2%
Na.sub.2CO.sub.3 solution, H.sub.2O and brine. The organic portion
was dried over Na.sub.2SO.sub.4, filtered and concentrated to give
a tan solid. Chromatography (SiO.sub.2, 5% MeOH/CHCl.sub.3) gave
2-ethoxymethyl-N.sup.1-isopropyl-1H-imidazo[4,5--
c]quinoline-1,4-diamine (368 mg) as a tan solid. mp 162-164.degree.
C.; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.60 (dd, J=8.2, 1.1
Hz, 1H), 7.77 (dd, J=8.4, 0.7 Hz, 1 H), 7.54-7.47 (m, 1 H),
7.33-7.24 (m, 1 H), 5.55 (d, J=3.2 Hz, 1 H), 5.41 (s, 2 H), 4.89
(s, 2 H), 3.73-3.60 (m, 3 H), 1.26 (t, J=7.0 Hz, 3H); 1.15 (d,
J=6.2 Hz, 6 H); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 151.1,
148.7, 145.0, 127.7, 126.6, 123.9, 121.9, 121.3, 115.4, 66.8, 65.7,
52.5, 20.6, 15.1; MS m/z 300 (M+H).sup.+; Anal. Calcd for
C.sub.16H.sub.21N.sub.5O.multidot.0.48 H.sub.2O: C, 62.39; H, 7.19;
N, 22.74; Found: C, 62.38; H, 6.90; N, 22.79.
Example 6
N.sup.1-Cyclohexyl-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline-1,4-diamine
[0795] 68
[0796] Part A
[0797] 2-(Ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-amine (0.900 g,
3.71 mmol) was placed in a 50 mL round bottom flask, dissolved in
1,2-dichloromethane, and placed under N.sub.2. Cyclohexanone (1.19
mL, 11.5 mmol), acetic acid (0.45 mL, 7.79 mmol) and sodium
triacetoxyborohydride (1.65 g, 7.79 mmol) were added and the
reaction was stirred under N.sub.2 at room temperature for 5 days.
The reaction was quenched by slow addition of saturated NaHCO.sub.3
solution (25 mL) and dichloromethane (25 mL). The mixture was
transferred to a separatory finnel and the phases separated. The
aqueous portion was extracted with dichloromethane (25 mL). The
combined organic portions were washed sequentially with water (25
mL) and brine (25 mL), dried (Na.sub.2SO.sub.4), filtered and then
concentrated to yield a thick brown oil. Analysis by liquid
chromatography/mass spectroscopy (LC/MS) of the crude product
showed it to be a mixture of the hydrazone and hydrazine. The oil
was dissolved in methanol (25 mL), chilled in an ice water bath and
then treated with sodium borohydride (1.25 g). The reaction was
quenched with water (25 mL) and the mixture concentrated. The
residue was partitioned between dichloromethane 50 mL) and water
(15 mL), transferred to a separatory funnel, and the phases were
separated. The organic portion was washed sequentially with
saturated NaHCO.sub.3 solution (20 mL), water (20 mL) and brine (20
mL), dried (Na.sub.2SO.sub.4), filtered and then concentrated to
yield a thick brown oil. The material was purified by column
chromatography (35 g SiO.sub.2, 97:3 chloroform:methariol) to yield
0.51 g of N-cyclohexyl-2-(ethoxymethyl)-1H-
-imidazo[4,5-c]quinolin-1-amine as a light brown oil/solid.
[0798] Part B
[0799]
N-Cyclohexyl-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-amine
(0.51 g, 1.57 mmol) was placed in a 200 mL round bottom flask,
purged with N.sub.2 and dissolved in dichloromethane (25 mL). MCPBA
(0.484 g, 1.96 mmol, 77% max) was added over a 5 min period. The
reaction was stirred at room temperature under N.sub.2. After 2 h,
analysis by thin layer chromatography (TLC) (SiO.sub.2, 95:5
chloroform:methanol) showed complete conversion. The solution was
diluted with dichloromethane (15 mL) and 2% sodium carbonate
solution (15 mL). The mixture was transferred to a separatory
funnel, and the phases were separated. The organic portion was
washed sequentially with 2% sodium carbonate solution (15 mL),
water (15 mL) and brine (15 mL), dried (Na.sub.2SO.sub.4), filtered
and then concentrated to yield 0.431 g of
N-cyclohexyl-2-(ethoxymethyl)-5-
-oxido-1H-imidazo[4,5-c]quinolin-1-amine as a tan foam.
[0800] Part C
[0801]
N-Cyclohexyl-2-(ethoxymethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-a-
mine (0.425 g, 1.25 mmol) was placed in a 100 mL round bottom flask
and dissolved in dichloromethane (20 mL). Ammonium hydroxide
solution (10 mL) was added and the mixture was stirred vigorously.
The stirred mixture was chilled in an ice water bath.
Para-toluenesulfonyl chloride (0.250 g, 1.31 mmol) was added over 5
min. After 30 min of stirring at 0.degree. C. TLC (SiO.sub.2, 95:5
chloroform:methanol) showed complete conversion. The mixture was
warmed to room temperature and then diluted with dichloromethane
(25 mL) and water (10 mL). The mixture was transferred to a
separatory funnel and the phases separated. The organic portion was
washed sequentially with 2% sodium carbonate solution (15 mL),
water (15 mL) and brine (15 mL), dried over Na.sub.2SO.sub.4,
filtered and then concentrated to yield an orange/tan foamy solid.
The material was purified by column chromatography (40 g SiO.sub.2,
95:5 chloroform:methanol) to yield the product as an off white
solid. The off-white solid was dissolved in 3 mL of a 9:1
chloroform:methanol mixture. A small spatula tip full of activated
carbon (DARCO G 60-100 mesh) was added and the mixture was stirred
at room temperature for 3 h. The mixture was filtered through a
short column of SiO.sub.2 (5 g) eluting with 9:1
chloroform:methanol. The filtrate was concentrated to yield a
glassy solid. The glassy solid was triturated in 15 mL diethyl
ether for 2 h to provide a white solid. The solid was collected by
vacuum filtration and rinsed with diethyl ether. The solid was
dried in a vacuum oven (70.degree. C.) to yield 0.062 g of
N.sup.1-cyclohexyl-2-(ethoxymeth-
yl)-1H-imidazo[4,5-c]quinoline-1,4-diamine. mp 143-145.degree. C.;
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.61 (dd, J=8.1, 1.1
Hz, 1 H), 7.58 (dd, J=8.3, 0.9 Hz, 1 H), 7.46-7.38 (m, 1 H),
7.28-7.21 (m, 1 H), 6.99 (d, J=1.9 Hz, 1 H), 6.69 (s, 2 H), 4.77
(s, 2 H), 3.63 (q, J=7.0 Hz, 2 H), 3.32-3.23 (m, 1H), 1.71-1.52 (m,
5 H), 1.30-1.05 (m, 8 H); .sup.13C NMR (75 MHz, DMSO-d.sub.6)
.delta.; MS m/z 152.1, 150.3, 145.0, 133.4, 127.4, 125.8, 123.9,
121.6, 121.1, 115.0, 65.8, 63.1, 59.8, 30.9, 25.8, 24.3, 15.4; MS
m/z 340 (M+H).sup.+; Anal. Calcd for C.sub.19H.sub.25N.sub.5O: C,
67.23; H, 7.42; N, 20.63; Found: C, 67.32; H, 7.37; N, 20.55.
Example 7
N.sup.1,N.sup.1-Dimethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1,4-dia-
mine
[0802] 69
[0803] Part A
[0804] A solution of 4-chloro-3-nitroquinoline (5.00 g, 24.0 mmol)
in 100 mL CH.sub.2Cl.sub.2 was cooled to 0.degree. C. and treated
with triethylamine (8.40 mL, 60.0 mmol) and N,N-dimethylhydrazine
(5.65 mL, 74.4 mmol) under an atmosphere of nitrogen. After 18 h,
the mixture was diluted with 2% Na.sub.2CO.sub.3 solution and
CHCl.sub.3 and separated. The organic portion was washed with water
and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure to yield
4-(2,2-dimethylhydrazino)-3-nitroquinoline (5.33 g) as a
yellow/orange crystalline solid.
[0805] Part B
[0806] A suspension of 4-(2,2-dimethylhydrazino)-3-nitroquinoline
(5.33 g, 23.0 mmol) in 125 mL of acetonitrile was treated with 5%
platinum on carbon (0.45 g, 0.11 mmol) and the mixture was shaken
under an atmosphere of hydrogen (3.8.times.10.sup.5 Pa). After 5 h,
the reaction mixture was filtered through a pad of CELITE filter
agent and rinsed with 80:20 acetonitrile:MeOH. The filtrate was
concentrated under reduced pressure. The resulting oil was
dissolved in CH.sub.2Cl.sub.2, dried over Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure to give
4-(2,2-dimethylhydrazino)quinolin-3-amine (4.64 g) as a red
foam.
[0807] Part C
[0808] A solution of 4- (2,2-dimethylhydrazino)quinolin-3-amine
(4.64 g, 23.0 mmol) in 75 mL of CH.sub.2Cl.sub.2 was cooled to
0.degree. C. under an atmosphere of nitrogen. The reaction mixture
was treated with triethylamine (6.72 mL, 48.2 mmol) followed by
dropwise addition of ethoxyacetyl chloride (2.95 g, 24.1 mmol).
After 1.5 h, the reaction mixture was concentrated under reduced
pressure. The resulting oil was dissolved in 75 mL of ethanol,
treated with triethylamine (9.60 mL, 68.9 mmol) and heated to
reflux. After 5 d, the reaction mixture was concentrated under
reduced pressure. The resulting oil was dissolved in
CH.sub.2Cl.sub.2, washed with 2% Na.sub.2CO.sub.3 solution, water
and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure to yield a brown oil. Chromatography
(SiO.sub.2, 5-10% MeOH/CHCl.sub.3) gave
N,N-dimethyl-2-(ethoxymethyl)-1H-imidazo[4,5-c]quin- olin-1-amine
(0.89 g) as a brown oil.
[0809] Part D
[0810] A solution of
N,N-dimethyl-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinol- in-1-amine
(0.89 g, 3.3 mmol) in 25 mL of CH.sub.2Cl.sub.2 was treated with
MCPBA (1.01 g, 4.10 mmol, 77% max). After 1.5 h, the reaction
mixture was treated with 7 mL of concentrated NH.sub.4OH solution
andp-toluenesulfonyl chloride (0.69 g, 3.6 mmol). After 30 min, the
reaction was diluted with CH.sub.2Cl.sub.2 and water and the phases
were separated. The organic portion was washed with 2%
Na.sub.2CO.sub.3 solution (2.times.), water and brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to yield an orange solid. Recrystallization twice from acetonitrile
gave
N.sup.1,N.sup.1-dimethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1,4-di-
amine (0.208 g) as gold, needle-like crystals. mp 213-215.degree.
C.; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.57 (dd, J=8.3, 1.4
Hz, 1 H), 7.79 (dd, J=8.4, 0.7 Hz, 1 H), 7.56-7.48 (m, 1 H),
7.38-7.29 (m, 1 H), 5.45 (s, 2 H), 4.48 (s, 2 H), 3.69 (q, J=7.0
Hz, 2 H), 3.20 (s, 6 H), 1.29 (t, J=7.0 Hz, 3 H); .sup.13C NMR (75
MHz, CDCl.sub.3) .delta. 151.2, 149.3, 145.1, 133.5, 127.7, 126.7,
123.8, 122.1, 115.3, 66.4, 65.6, 45.3, 15.1; MS (APCI) m/z 286
(M+H).sup.+; Anal. Calcd for C.sub.15H.sub.19N.sub.5O: C, 63.14; H,
6.71; N, 24.54; Found: C, 63.02; H, 6.91; N, 24.57.
Example 8
2-Ethoxymethyl-N.sup.1-(furan-2-ylmethyl)-1H-imidazo[4,5-c]quinoline-1,4-d-
iamine
[0811] 70
[0812] Part A
[0813] A solution of
2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-amine (1.50 g, 6.19
mmol) in 20 mL of isopropanol was treated with 2-furaldehyde (1.08
mL, 13.0 mmol) and 2 drops of concentrated HCl and heated to reflux
under an atmosphere of nitrogen. After 48 h, the reaction was
concentrated under reduced pressure to yield a brown oil. The oil
was dissolved in 30 mL of CHCl.sub.3 and washed with 5%
Na.sub.2CO.sub.3 solution, water and brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to yield
N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)(furan-2-ylmethylene)ami-
ne (1.86 g) as a light brown solid.
[0814] Part B
[0815] A solution of
N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)(fur-
an-2-ylmethylene)amine (1.86 g, 5.81 mmol) in 20 mL of methanol was
treated with NaBH.sub.4 (0.659 g, 17.4 mmol) and stirred under an
atmosphere of nitrogen. After 18 h the reaction was quenched by
addition of 20 mL of water. The reaction mixture was concentrated
under reduced pressure and dissolved in CHCl.sub.3. The organic
portion was washed with 2% Na.sub.2CO.sub.3 solution, water and
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure to yield
N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)(furan-2-ylmethyl)-
amine (1.70 g) as a thick orange syrup.
[0816] Part C
[0817] A solution of
N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)(fur-
an-2-ylmethyl)amine (1.70 g, 5.27 mmol) in 45 mL of
CH.sub.2Cl.sub.2 was treated with MCPBA (1.48 g, 6.59 mmol, 77%
max). After 1.5 h the reaction mixture was treated with 15 mL of
concentrated NH.sub.4OH solution and p-toluenesulfonyl chloride
(1.06 g, 5.54 mmol). After 45 min the reaction mixture was diluted
with water and CHCl.sub.3 and separated. The organic portion was
washed with 3% Na.sub.2CO.sub.3 solution, water and brine, dried
over Na.sub.2SO.sub.4, and concentrated under reduced pressure to
yield a yellow foam. Chromatography (SiO.sub.2, 95:5
CHCl.sub.3:MeOH) gave an off white foam. The foam was triturated
with diethyl ether and filtered to give
2-ethoxymethyl-N.sup.1-(furan-2-ylmethyl)-1H-imidazo[4,5-
-c]quinoline-1,4-diamine (1.03 g) as an off white powder. mp dec.
>200.degree. C.; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.57
(dd, J=8.1, 1.1 Hz, 1 H), 7.80 (dd, J=8.4, 0.8 Hz, 1 H), 7.57-7.51
(m, 1H), 7.45 (d, J=1.8 Hz, 1 H), 7.39-7.33 (m, 1 H), 6.34-6.32 (m,
1 H), 6.24 (t, J=5.3 Hz, 1 H), 6.07 (d, J=3.1 Hz, 1 H), 5.43 (s, 2
H), 4.40-4.38 (m, 4 H), 3.57 (q, J=7.0 Hz, 2 H), 1.25 (t, J=7.0 Hz,
3 H); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 151.1, 149.5,
147.8, 144.8, 143.0, 132.6, 127.8, 126.6, 124.1, 122.5, 120.7,
115.1, 111.1, 110.1, 66.8, 64.9, 48.5, 15.0; MS (APCI) m/z 338
(M+H).sup.+; Anal. Calcd for C.sub.18H.sub.19N.sub.5O.s- ub.2: C,
64.08; H, 5.68; N, 20.76; Found: C, 63.89; H, 5.75; N, 20.48.
Example 9
2-Ethoxymethyl-N.sup.1-(1-ethylpropyl)-1H-imidazo[4,5-c]quinoline-1,4-diam-
ine
[0818] 71
[0819] Part A
[0820] A solution of
2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-amine (1.50 g, 6.19
mmol) in 20 mL of toluene and 5 mL of isopropanol was treated with
3-pentanone (5.00 mL, 47.2 mmol) and pyridiniump-toluenesulf- onate
(0.015 g, 0.062 mmol) and the reaction mixture was heated to reflux
under an atmosphere of nitrogen. After 7 d, the reaction mixture
was concentrated under reduced pressure, dissolved in CHCl.sub.3,
washed with water (2.times.) and brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to yield a light brown oil. Chromatography (SiO.sub.2, 95:5
CHCl.sub.3:MeOH) gave
N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)(1-ethylpropylidene)amin-
e (1.78 g) as a yellow/green syrup.
[0821] Part B
[0822] A solution of
N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)(1-e-
thylpropylidene)amine (1.78 g, 5.73 mmol) in 20 mL of methanol was
treated with NaBH.sub.4 (0.867 g, 22.9 mmol) and
CeCl.sub.37H.sub.2O (15 mg, catalytic) and stirred under an
atmosphere of nitrogen. After 24 h, the reaction was concentrated
under reduced pressure, dissolved CHCl.sub.3, washed with water
(2.times.) and brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to yield a yellow/green syrup.
Chromatography (SiO.sub.2, 93:7 CHCl.sub.3 :MeOH) gave
N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)(1-ethylpropyl)amine
(1.01 g) as a yellow/green oil.
[0823] Part C
[0824] A solution of
N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)(1-e-
thylpropyl)amine (1.01 g, 3.23 mmol) in 30 mL of CH.sub.2Cl.sub.2
was treated with MCPBA (1.04 g, 4.20 mmol, 77% max). After 1.5 h
the reaction mixture was treated with 15 mL of concentrated
NH.sub.4OH solution andp-toluenesulfonyl chloride (0.65 g, 3.39
mmol). After 30 min, the reaction mixture was diluted with
CH.sub.2Cl.sub.2 and water and the phases were separated. The
organic portion was washed with 2% Na.sub.2CO.sub.3 solution and
water. The combined aqueous washes were back extracted with
CHCl.sub.3 (2.times.). The combined organic portions were washed
with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure to yield a light yellow foam. Chromatography
(SiO.sub.2, 97:3 CHCl.sub.3:MeOH) gave a white foam. The foam was
triturated with CH.sub.2Cl.sub.2/hexanes and filtered to give
2-ethoxymethyl-N-(1-ethylpropyl)-1H-imidazo[4,5-c]quinoline-1,4-diamine
(0.652 g) as a white solid. mp 125-128.degree. C.; .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.66 (dd, J=8.3, 1.1 Hz, 1 H), 7.77 (dd,
J=7.6, 0.8 Hz, 1 H), 7.55-7.48 (m, 1 H), 7.33-7.26 (m, 1 H), 5.66,
(d, J=3.0 Hz, 1 H), 5.41 (s, 2 H), 4.87 (s, 2 H), 3.64 (q, J=7.0
Hz, 2 H), 3.32-3.23 (m, 1 H), 1.70-1.56 (m, 2 H), 1.55-1.41 (m, 2
H), 1.27 (t, J=7.1 Hz, 3 H), 0.94 (t, J=7.5 Hz, 6 H); .sup.13C NMR
(75 MHz, CDCl.sub.3) .delta. 151.5, 149.1, 145.4, 135.0, 132.4,
128.1, 126.9, 124.1, 122.2, 122.0, 115.9, 67.2, 66.2, 64.0, 24.5,
15.5, 10.2; MS (APCI) m/z 328 (M+H).sup.+; Anal. Calcd for
C.sub.18H.sub.25N.sub.5O: C, 66.03; H, 7.70; N, 21.39; Found: C,
65.64; H, 7.89; N, 21.02.
Example 10
2-Ethoxymethyl-N.sup.1-isobutyl-1H-imidazo[4,5-c]quinoline-1,4-diamine
[0825] 72
[0826] Part A
[0827] A solution of
2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-amine (0.940 g, 3.88
mmol) in 20 mL of toluene and 5 mL of isopropanol was treated with
isobutyraldehyde (0.800 mL, 8.81 mmol) and
pyridiniump-toluenesulfonate (0.098 g, 0.39 mmol) and the reaction
mixture was heated to reflux under an atmosphere of nitrogen. After
48 h, the reaction mixture was concentrated under reduced pressure
and dissolved in CHCl.sub.3. The organic portion was washed with
water (2.times.) and brine, dried over Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure to yield a light brown oil
which solidified under vacuum to yield
N-(2-ethoxymethyl-1H-imidazo[4,5-c]quino-
lin-1-yl)isobutylideneamine (1.15 g) as a tan solid.
[0828] Part B
[0829] A solution of
N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)isob-
utylideneamine (1.15 g, 3.88 mmol) in 15 mL of methanol was treated
with NaBH.sub.4 (0.44 g, 11.6 mmol) and stirred under an atmosphere
of nitrogen. After 18 h, the reaction was concentrated under
reduced pressure. The residue was partitioned between CHCl.sub.3
and water, and the phases were separated. The organic portion was
washed with water and brine, dried over Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure to yield an orange oil.
Chromatography (SiO.sub.2, 97:3 CHCl.sub.3:MeOH), gave
N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)i- sobutylamine
(0.69 g) as clear, colorless crystals.
[0830] Part C
[0831] A solution of
N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)isob- utylamine
(1.16 g, 3.89 mmol) in 30 mL of CH.sub.2Cl.sub.2 was treated with
MCPBA (1.25 g, 5.05 mmol, 77% max). After 1.5 h, the reaction
mixture was treated with 15 mL of concentrated NH.sub.4OH solution
andp-toluenesulfonyl chloride (0.78 g, 4.08 mmol). After 30 min the
reaction mixture was diluted with CH.sub.2Cl.sub.2 and water, and
the phases were separated. The organic portion was washed with 2%
Na.sub.2CO.sub.3 solution and water. The combined aqueous washes
were back extracted with CHCl.sub.3 (2.times.). The combined
organic portions were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to yield a brown foam. Chromatography (SiO.sub.2, 97:3
CHCl.sub.3:MeOH) yielded 2-ethoxymethyl-N.sup.1-isobutyl-
-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.049 g) as an off white
solid. mp 137-140.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6,
350 K) .delta. 8.47 (dd, J=8.1, 0.9 Hz, 1 H), 7.60 (d, J=8.3 Hz, 1
H), 7.45-7.36 (m, 1H), 7.28-7.19 (m, 1 H), 6.67, (t, J=6.2 Hz, 1
H), 6.22 (s, 2 H), 4.76 (s, 2 H), 3.64 (q, J=7.0 Hz, 2 H), 3.02 (t,
J=6.4 Hz, 2 H), 1.97 (s, J=6.7 Hz, 1 H), 1.19 (t, J=7.0 Hz, 3 H),
1.05 (dJ=6.7 Hz, 6 H); .sup.13C NMR (75 MHz, DMSO-d.sub.6) .delta.
151.9, 148.9, 144.8, 131.9, 126.9, 125.7, 123.8, 120.8, 114.2,
65.4, 62.8, 59.6, 26.7, 20.5, 14.9; MS (APCI) m/z 314 (M+H).sup.+;
Anal. Calcd for C.sub.17H.sub.23N.sub.5O: C, 65.15; H, 7.40; N,
22.35; Found: C, 64.88; H, 7.39; N, 22.38.
Example 11
2-Ethoxymethyl-N.sup.1-isopropyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quino-
line-1,4-diamine
[0832] 73
[0833] Part A
[0834] A solution of
2-ethoxymethyl-N.sup.1-isopropyl-1H-imidazo[4,5-c]qui- noline-1,4-
diamine (0.700 g, 2.34 mmol) in 25 mL of trifluroacetic acid was
treated with platinum(IV) oxide (0.27 g, 1.2 mmol) and the mixture
was shaken under an atmosphere of hydrogen (3.8.times.10.sup.5 Pa).
After 15 h, the reaction mixture was filtered through a pad of
CELITE filter agent, rinsed with 9:1:0.5
CHCl.sub.3:MeOH:trifluoroacetic acid (TFA) and concentrated under
reduced pressure to yield a creamy white solid. The solid was
triturated with concentrated NH.sub.4OH solution for 2 h and then
extracted with CHCl.sub.3 (3.times.). The organic portion was
washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to yield a white foam. The foam
was triturated with diethyl ether, filtered and dried under reduced
pressure to yield
2-ethoxymethyl-N.sup.1-isopropyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quin-
oline-1,4-diamine (0.376 g) as a fine white solid. mp
144-146.degree. C.; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 5.08
(d, J=2.7 Hz, 1 H), 4.92 (s, 2 H), 4.78 (s, 2 H), 3.61 (q, J=7.0
Hz, 2 H), 3.53-3.43 (m, 1 H), 3.07-3.03 (m, 2 H), 2.85-2.81 (m, 2
H), 1.92-1.79 (m, 4 H), 1.25 (t, J=7.0 Hz, 3 H), 1.08 (d, J=6.3 Hz,
6 H); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 149.4, 148.9,
148.1, 138.8, 122.9, 107.4, 66.6, 65.4, 53.0, 32.5, 23.7, 23.2,
22.8, 20.5, 15.1; MS (APCI) m/z 304 (M+H).sup.+; Anal. Calcd for
C.sub.16H.sub.25N.sub.5O: C, 63.34; H, 8.31; N, 23.08; Found: C,
63.32; H, 8.31; N, 22.97.
Example 12
2-Ethoxymethyl-N.sup.1-(3-methylbutyl)-1H-imidazo[4,5-c]quinoline-1,4-diam-
ine
[0835] 74
[0836] Part A
[0837] A solution of
2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-amine (1.00 g, 4.13
mmol) in 20 mL of toluene and 5 mL of isopropanol was treated with
isovaleraldehyde (0.94 mL, 8.76 mmol) and
pyridiniump-toluenesulfonate (0.052 g, 0.21 mmol) and the reaction
mixture was heated to reflux under an atmosphere of nitrogen. After
15 h, the reaction mixture was concentrated under reduced pressure
to yield a brown oil. The oil was dissolved in CHCl.sub.3 and
washed with water (2.times.) and brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to yield N-(2-ethoxymethyl-1H-imidazo-
[4,5-c]quinolin-1-yl)(3-methylbutylidene)amine (1.28 g) as a dark
orange oil.
[0838] Part B
[0839] A solution of
N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)(3-m-
ethylbutylidene)amine (1.28 g, 4.13 mmol) in 25 mL of methanol was
treated with NaBH.sub.4 (0.47 g, 12.39 mmol). After 1 h, the
reaction was quenched with saturated NH.sub.4Cl solution and the
mixture was concentrated under reduced pressure. The residue was
partitioned between CHCl.sub.3 and saturated NaHCO.sub.3 solution
and the phases were separated. The organic portion was washed with
water and brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to yield
N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)(3-methylbutyl)-
amine (1.24 g) as a dark orange oil.
[0840] Part C
[0841] A solution of
N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)(3-m-
ethylbutyl)amine (1.24 g, 3.97 mmol) in 45 mL of CH.sub.2Cl.sub.2
was treated with MCPBA (1.87 g, 7.04 mmol, 77% max). After 1.5 h,
the reaction mixture was treated with 15 mL of concentrated
NH.sub.4OH solution and p-toluenesulfonyl chloride (0.795 g, 4.17
mmol). After 30 min, the reaction mixture was diluted with
CHCl.sub.3 and water and the phases were separated. The organic
portion was washed with 5% Na.sub.2CO.sub.3 solution, water and
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure to yield a sticky orange foam. Chromatography
(SiO.sub.2, 97:3 CHCl.sub.3:MeOH) gave an off white foam. The foam
was triturated with diethyl ether and hexanes and filtered to give
2-ethoxymethyl-N-(3-methylbutyl)-1H-imidazo[4,5-c]quinoline-1,4-d-
iamine (0.435 g) as a cream colored solid. mp 129-132.degree. C.;
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.48 (dd, J=8.1, 1.1 Hz,
1 H), 7.78 (d, J=8.3 Hz, 1 H), 7.56-7.50 (m, 1 H), 7.36-7.30 (m, 1
H), 5.59 (t, J=6.7 Hz, 1 H), 5.42 (s, 2 H), 4.87 (s, 2 H), 3.64 (q,
J=7.0 Hz, 2 H), 3.29 (q, J=7.0 Hz, 2 H), 1.76 (s, J=6.7 Hz, 1 H),
1.60 (q, J=6.9 Hz, 2 H), 1.27 (t, J=7.0 Hz, 3 H), 0.97 (d, J=6.6
Hz, 6 H); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 151.2, 147.8,
144.9, 133.1, 127.8, 126.6, 124.0, 122.3, 120.7, 115.2, 66.8, 65.3,
51.1, 36.7, 26.0, 22.6, 15.1; MS (APCI) m/z 328 (M+H).sup.+; Anal.
Calcd for C.sub.18H.sub.25N.sub.5O.multidot.0.- 06H.sub.2O: C,
65.81; H, 7.71; N, 21.32; Found: C, 65.42; H, 7.75; N, 21.11. Karl
Fischer analysis 0.32% water.
Example 13
2-Ethoxymethyl-1-(morpholin-4-yl)-1H-imidazo[4,5-c]quinolin-4-amine
[0842] 75
[0843] Part A
[0844] A solution of 4-chloro-3-nitroquinoline (5.00 g, 24.0 mmol)
in 100 mL of CH.sub.2Cl.sub.2 was treated with triethylamine (6.37
mL, 48.0 mmol) and 4-aminomorpholine (3.47 mL, 36.0 mL) under an
atmosphere of nitrogen. After 15 h, the reaction mixture was
diluted with 5% Na.sub.2CO.sub.3 solution and CHCl.sub.3, and the
phases were separated. The organic portion was washed with another
portion of 5% Na.sub.2CO.sub.3 solution, water and brine, dried
over Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure to yield a bright yellow solid. Recrystallization from
acetonitrile gave N-(morpholin-4-yl)(3-nitr- oquinolin-4-yl)amine
(4.54 g) as bright yellow needle-like crystals.
[0845] Part B
[0846] A solution of N-(morpholin-4-yl)(3-nitroquinolin-4-yl)amine
(4.54 g, 16.6 mmol) in 150 mL of toluene was treated with 5%
platinum on carbon (0.65 g, 0.17 mmol) and the mixture was shaken
under an atmosphere of hydrogen (3.8.times.10.sup.5 Pa). After 15
h, the reaction mixture was filtered through a pad of CELITE filter
agent and rinsed with 4:1 toluene:MeOH. The filtrate was
concentrated under reduced pressure to yield
N.sup.4-(morpholin-4-yl)quinoline-3,4-diamine (4.06 g) as a red
foam.
[0847] Part C
[0848] A solution of N.sup.4-(morpholin-4-yl)quinoline-3,4-diamine
(4.06 g, 16.6 mmol) in 50 mL of CH.sub.2Cl.sub.2 was treated with
triethylamine (4.40 mL, 33.2 mmol) and cooled to 0.degree. C. The
solution was treated dropwise with ethoxyacetyl chloride (2.40 g,
17.4 mmol) and stirred under an atmosphere of nitrogen. The
reaction mixture was allowed to slowly come to room temperature.
After 2 d, the reaction mixture was concentrated under reduced
pressure to yield a red semi-solid. The material was dissolved in
CHCl.sub.3 and washed with water, 5% Na.sub.2CO.sub.3 solution and
brine, dried over Na.sub.2SO.sub.4, filtered and dried to yield
2-ethoxy-N-{4-[(morpholin-4-yl)amino]quinolin- -3-yl}acetamide
(5.35 g) as a red/orange foam.
[0849] Part D
[0850] A suspension of
2-ethoxy-N-{4-[(morpholin-4-yl)amino]quinolin-3-yl}- acetamide
(5.35 g, 16.2 mmol) in 65 mL of toluene was treated with pyridine
hydrochloride (0.94 g g, 0.081 mmol). The reaction flask was
equipped with a Dean-Stark trap and the reaction mixture was heated
to reflux under an atmosphere of nitrogen. After 2.5 d, the
reaction mixture was concentrated under reduced pressure to yield a
brown oil. The oil was dissolved in CHCl.sub.3 and was washed with
5% Na.sub.2CO.sub.3 solution, water and brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to yield a brown foam. Chromatography (SiO.sub.2, 95:5
CHCl.sub.3:MeOH) gave
2-ethoxymethyl-1-(morpholin-4-yl)-1H-imidazo[4- ,5-c]quinoline
(1.61 g) as a light brown solid.
[0851] Part E
[0852] A solution of
2-ethoxymethyl-1-(morpholin-4-yl)-1H-imidazo[4,5-c]qu- inoline
(1.61 g, 5.51 mmol) in 40 mL of CH.sub.2Cl.sub.2 was treated with
MCPBA (1.78 g, 6.70 mmol, 77% max). After 30 min, the reaction
mixture was treated with 20 mL of concentrated NH.sub.4OH solution
and p-toluenesulfonyl chloride (1.03 g, 5.41 mmol). After 15 min,
the reaction mixture was diluted with CH.sub.2Cl.sub.2 and water
and the phases were separated. The organic portion was washed with
5% Na.sub.2CO.sub.3 solution, water and brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to yield a tan foam. Chromatography (SiO.sub.2, 97:3
CHCl.sub.3:MeOH) gave a light yellow foam. The foam was triturated
with diethyl ether and filtered to give
2-ethoxymethyl-1-(morpholin-4-yl)-1H-imidazo[4,5-c]quinolin-4-amine
(0.794 g) as a light cream colored solid. mp 223-224.degree. C.;
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.77 (d, J=8.1 Hz, 1 H),
7.79 (d, J=8.4 Hz, 1 H), 7.54 (t, J=8.2 Hz, 1 H), 7.34 (t, J=8.1
Hz, 1 H), 5.48 (s, 2 H), 4.85 (s, 2 H), 4.06-4.03 (m, 4 H),
3.74-3.66 (m, 4 H), 3.42-3.38 (m, 2 H), 1.29 (t, J=7.0 Hz, 3 H);
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 151.2, 149.0, 145.3,
133.5, 127.9, 126.9, 123.7, 122.2, 121.3, 115.3, 67.5, 66.5, 65.9,
53.5, 15.1; MS (APCI) m/z 328 (M+H).sup.+; Anal. Calcd for
C.sub.17H.sub.21N.sub.5O.sub.2: C, 62.37; H, 6.47; N, 21.39; Found:
C, 62.14; H, 6.19; N, 21.34.
Example 14
N-{3-[(4-Amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)amino]propyl}-
methanesulfonamide
[0853] 76
[0854] Part A
[0855] A solution of 1-amino-3,3-diethoxypropane (5.00 mL, 30.9
mmol) in 5 mL of tetrahydrofuran (THF) was treated with
triethylamine (4.51 mL, 34.0 mmol) under an atmosphere of nitrogen
and cooled to 0.degree. C. The reaction mixture was then treated
dropwise with a solution of di-tert-butyl dicarbonate (7.42 g, 34.0
mmol) in 25 mL of THF. The reaction mixture was stirred for 2 h at
0.degree. C. and then allowed to come to room temperature. After 15
h, the reaction mixture was concentrated under reduced pressure,
dissolved in ethyl acetate, washed with water (2.times.) and brine,
dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure to yield tert-butyl (3,3-diethoxypropyl)carbamate
(8.40 g) as a clear, faintly yellow oil.
[0856] Part B
[0857] A solution of
2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-amine (1.00 g, 4.13
mmol) in 20 mL of acetonitrile and 5 mL of glacial acetic acid was
treated with tert-butyl (3,3-diethoxypropyl)carbamate (2.55 g, 10.3
mmol) and heated to reflux under an atmosphere of nitrogen. After
15 h, the reaction mixture was concentrated under reduced pressure
to yield a brown oil. The oil was partitioned between CHCl.sub.3
and saturated NaHCO.sub.3 solution and the phases were separated.
The organic portion was washed with water (2.times.) and brine,
dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure to yield tert-butyl
{3-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)imino]propyl}carbamate
(1.64 g) as a dark red/orange oil.
[0858] Part C
[0859] A solution of tert-butyl
{3-[(2-ethoxymethyl-1H-imidazo[4,5-c]quino-
lin-1-yl)imino]propyl}carbamate (1.64 g, 4.13 mmol) in 20 mL of
methanol was treated with NaBH.sub.4 (0.78 g, 20.6 mmol) under an
atmosphere of nitrogen. After 1.5 h, the reaction mixture was
quenched with saturated NH.sub.4Cl solution and concentrated under
reduced pressure. The residue was partitioned between saturated
NaHCO.sub.3 solution and CHCl.sub.3 and the phases were separated.
The organic portion was washed with water and brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to yield a light brown solid. Chromatography [SiO.sub.2, 95:5
CHCl.sub.3:(80:18:2 CHCl.sub.3:MeOH:NH.sub.4OH)] yielded tert-butyl
{3-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)amino]propyl}carbamate
(1.34 g) as a tan foam.
[0860] Part D
[0861] A solution of tert-butyl
{3-[(2-ethoxymethyl-1H-imidazo[4,5-c]quino-
lin-1-yl)amino]propyl}carbamate (1.34 g, 3.35 mmol) in 30 mL of
CHCl.sub.3 was treated with MCPBA (1.45 g, 5.03 mmol, 77% max).
After 3 h, the reaction mixturewas diluted with 10%
Na.sub.2CO.sub.3 solution and CHCl.sub.3 and the phases were
separated. The organic portion was washed with water and brine,
dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure to yield tert-butyl
{3-[(2-ethoxymethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)amino]propyl}c-
arbamate (1.39 g) as an orange foam.
[0862] Part E
[0863] A solution of tert-butyl
{3-[(2-ethoxymethyl-5-oxido-1H-imidazo[4,5-
-c]quinolin-1-yl)amino]propyl}carbamate (1.39 g, 3.35 mmol) in 35
mL of CHCl.sub.3 was treated with 15 mL of concentrated NH.sub.4OH
solution and p-toluenesulfonyl chloride (0.67 g, 3.51 mmol). After
15 min, the reaction mixture was diluted with water and CHCl.sub.3
and the phases were separated. The organic portion was washed with
10% Na.sub.2CO.sub.3 solution and water. The combined aqueous
washes were back-extracted with. CHCl.sub.3. The combined organic
extracts were washed with brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure to yield
{3-[(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)amino-
]propyl} tert-butyl carbamate (1.30 g) as an orange foam.
[0864] Part F
[0865] A solution of
{3-[(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-
-1-yl)amino]propyl} tert-butyl carbamate (1.30 g, 3.14 mmol) in 10
mL of ethanol was treated with a solution of 3 M hydrogen chloride
in ethanol (5.0 mL, 15 mmol) and heated to 100.degree. C. After 30
min, the solvent was concentrated under reduced pressure to yield a
brown sludge. The material was triturated with diethyl ether and
filtered to give a tan solid. The solid was dissolved in water and
treated with 10% NaOH solution until pH 13 was reached. The aqueous
solution was extracted with CH.sub.2Cl.sub.2 (4.times.). The
combined organic extracts were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to yield N.sup.1-(3-aminopropyl)-2-ethoxymethyl-1H-imida-
zo[4,5-c]quinoline-1,4-diamine (0.77 g) as a gold colored foam.
[0866] Part G
[0867] A solution of
N.sup.1-(3-aminopropyl)-2-ethoxymethyl-1H-imidazo[4,5-
-c]quinoline-1,4-diamine (0.250 g, 0.795 mmol) in 10 mL of
CH.sub.2Cl.sub.2 was treated with triethylamine (0.221 mL, 1.67
mmol) under an atmosphere of nitrogen and cooled to 0.degree. C.
The reaction mixture was treated dropwise with methanesulfonyl
chloride (0.065 mL, 0.835 mmol). After 16 h, the reaction mixture
was quenched by 10% Na.sub.2CO.sub.3 solution, diluted with
CHCl.sub.3 and the phases were separated. The organic portion was
washed with water and brine, dried over Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure to yield a light yellow
solid. Chromatography (SiO.sub.2, 95:5 CHCl.sub.3:MeOH) gave an
off-white foam. The foam was triturated with diethyl ether and
filtered to give N-{3-[(4-amino-2-ethoxymethyl-1H-imida-
zo[4,5-c]quinolin-1-yl)amino]propyl} methanesulfonamide (0.164 g)
as an off white solid. mp 148-150.degree. C.; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 8.46 (d, J=7.8 Hz, 1 H), 7.58 (d, J=8.2 Hz, 1
H), 7.44 (t, J=7.1 Hz, 1 H), 7.25 (t, J=7.4 Hz, 1 H), 7.05-6.95 (m,
2 H), 6.61 (s, 2 H), 4.76 (s, 2 H), 3.62 (q, J=7.0 Hz, 2 H), 3.22
(q, J=6.8 Hz, 2 H), 3.07 (q, J=6.2 Hz, 2 H), 2.88 (s, 3 H), 1.78
(p, J=6.3 Hz, 2 H), 1.18 (t, J=7.0 Hz, 3 H); .sup.13C NMR (125 MHz,
DMSO-d.sub.6) .delta. 152.3, 149.5, 145.3, 132.5, 127.4, 126.1,
124.2, 121.3, 121.3, 114.7, 65.9, 63.1, 49.9, 39.6, 28.1, 15.4; MS
(APCI) m/z 393 (M+H).sup.+; Anal. Calcd for
C.sub.17H.sub.24N.sub.6O.sub.3: C, 52.03; H, 6.16; N, 21.41; Found:
C, 51.84; H, 6.28; N, 21.18.
Example 15
1-{3-[(4-Amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)amino]propyl}-
-3-phenylurea
[0868] 77
[0869] Part A
[0870] A solution of
N.sup.1-(3-aminopropyl)-2-ethoxymethyl-1H-imidazo[4,5-
-c]quinoline-1,4-diamine (0.250 g, 0.795 mmol) in 10 mL of
CH.sub.2Cl.sub.2 was cooled to 0.degree. C. under an atmosphere of
nitrogen. The reaction mixture was treated dropwise with phenyl
isocyanate (0.091 mL, 0.835 mmol). After 16 h, the reaction mixture
was quenched by 10% Na.sub.2CO.sub.3 solution, diluted with
CHCl.sub.3 and the phases were separated. The organic portion was
washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to yield an off-white solid.
Chromatography (SiO.sub.2, 95:5 CHCl.sub.3:MeOH) gave an off-white
foam. The foam was triturated with diethyl ether and filtered to
give 1-{3-[(4-amino-2-ethoxymethyl-1H-imida-
zo[4,5-c]quinolin-1-yl)amino]propyl}-3-phenylurea (0.115 g) as an
off-white solid. mp 177-179.degree. C.; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 8.46 (dd, J=8.1, 1.0 Hz, 1 H), 8.39 (s, 1 H),
7.58 (dd, J=8.4, 0.9 Hz, 1 H), 7.44-7.35 (m, 3 H), 7.25-7.18 (m, 3
H), 6.99 (t, J=5.6 Hz, 1 H), 6.90-6.85 (m, 1 H), 6.60 (s, 2 H),
6.16 (t, J=5.6 Hz, 1 H), 4.76 (s, 2 H), 3.60 (q, J=7.0 Hz, 2 H),
3.26-3.18 (m, 4 H), 1.76 (t, J=7.0 Hz, 2 H), 1.15 (t, J=7.0 Hz, 3
H); .sup.13C NMR (125 MHz, DMSO-d.sub.6) .delta. 155.2, 151.8,
149.0, 144.8, 140.4, 132.0, 128.5, 126.9, 125.7, 123.7, 120.9,
120.8, 120.8, 117.6, 114.3, 65.4, 62.7, 49.7, 37.0, 28.1, 14.9; MS
(APCI) m/z 434 (M+H).sup.+; Anal. Calcd for
C.sub.23H.sub.27N.sub.7O.sub.2: C, 63.72; H, 6.28; N, 22.62; Found:
C, 63.45; H, 6.04; N, 22.28.
Example 16
N.sup.1-Isopropyl-2-propyl-1H-imidazo[4,5-c]quinoline-1,4-diamine
[0871] 78
[0872] Part A
[0873] A suspension of N'-(3-aminoquinolin-4-yl)hydrazine
tert-butyl carboxylate (6.50 g, 23.7 mmol) in 100 mL of toluene was
treated with trimethyl orthobutyrate (4.18 mL, 26.1 mmol) and
pyridine hydrochloride (0.14 g, 1.2 mmol) and heated to 130.degree.
C. under an atmosphere of nitrogen. After 18 h, the reaction
mixture was concentrated under reduced pressure to yield abrown
oil. The oil was dissolved in 150 mL CHCl.sub.3, washed with water
(2.times.50 mL), brine (50 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure to give 7.23 g of
tert-butyl (2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)carbam- ate as
an orange foam.
[0874] Part B
[0875] A solution of tert-butyl
(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)c- arbamate (7.23 g, 22.2
rnmol) in 40 mL of ethanol was treated with HCl (37 mL, 111 mmol, 3
M in ethanol) and heated to reflux. After 1 h, the reaction mixture
was cooled to ambient temperature, diluted with 80 mL of diethyl
ether, and cooled in an ice water bath. The HCl salt of the product
was collected by vacuum filtration and rinsed with diethyl ether
until the filtrate ran clear. The dried HCl salt was dissolved in
75 mL of water and treated with 50% NaOH solution until the pH of
the water was 12-13. The free base of the product precipitated out
and was triturated in the basic water for 30 min while being cooled
in an ice water bath. The solid was collected by vacuum filtration
and dried under vacuum to give 4.64 g of
2-propyl-1H-imidazo[4,5-c]quinolin-1-amine as a tan granular
solid.
[0876] Part C
[0877] A solution of 2-propyl-1H-imidazo[4,5-c]quinolin-1-amine
(4.64 g, 20.5 mmol) in 60 mL of acetonitrile and 15 mL of glacial
acetic acid was treated with 2,2-dimethoxypropane (12.6 mL, 103
mmol) and heated to 100.degree. C. under an atmosphere of nitrogen.
After 6 d, the reaction mixture was concentrated under reduced
pressure to yield a brown oil. The oil was dissolved in 100 mL of
CHCl.sub.3 and washed with 10% Na.sub.2CO.sub.3 (2.times.25 mL),
water (25 mL), brine (25 mL), dried over Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure to give 4.30 g of
N-isopropylidene-(2-propyl-1H-imidazo[4,5-c]quinolin-1-- yl)amine
as a brown oil.
[0878] Part D
[0879] A solution of
N-isopropylidene-(2-propyl-1H-imidazo[4,5-c]quinolin-- 1-yl)amine
(4.30 g, 16.1 mmol) in 100 mL of methanol was cooled in an ice
water bath. The solution was treated with sodium borohydride (3.05
g, 80.7 mmol) over 5 min. The reaction mixture was allowed to warm
to ambient temperature. After 2.5, the reaction was quenched by
addition of 15 mL of saturated NH.sub.4Cl solution. The mixture was
concentrated under reduced pressure to yield a light brown solid.
The solid was partitioned between 100 mL CHCl.sub.3 and 25 mL of
saturated NaHCO.sub.3 solution and then separated. The organic
portion was washed with water (25 mL), brine (25 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to yield a light brown solid. The solid was purified by
chromatography (SiO.sub.2, 97:2.5:0.5 CHCl.sub.3:MeOH:NH.sub.4OH)
to give 2.48 g of N-isopropyl-(2-propyl-1H-im-
idazo[4,5-c]quinolin-1-yl)amine as a tan solid.
[0880] Part E
[0881] A solution of
N-isopropyl-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)- amine (2.48
g, 9.24 mmol) in 75 mL of chloroform was cooled in a cold water
bath. The solution was treated with MCPBA (3.32 g, 11.6 mmol) over
6 min. The reaction was allowed to come to ambient temperature.
After 1.5 h, TLC showed complete conversion to the 5-N-oxide
intermediate. The reaction mixture was again cooled in a cold water
bath and then treated with concentrated ammonium hydroxide solution
(30 mL, 30%) and stirred rapidly. The reaction mixture was treated
with p-toluenesulfonyl chloride (1.85 g, 9.70 mmol) over 5 min. The
reaction was allowed to come to ambient temperature. After 30 min,
the reaction mixture was diluted with 50 mL of chloroform and 30 mL
of water and the phases were separated. The organic portion was
washed with 5% Na.sub.2CO.sub.3 solution (30 mL), water (30 mL) and
brine (30 mL). The organic portion was dried over Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure to yield a light
brown foam. The material was purified by chromatography (SiO.sub.2,
97:3 CHCl.sub.3:MeOH) and recrystallized from EtOAc to yield 1.39 g
of N.sup.1-isopropyl-2-propyl-1H-imidazo[4,5-c]quinoline-1,4-diami-
ne as amber crystals.
[0882] mp 181-184.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 8.44 (d, J=8.1 Hz, 1 H), 7.57 (d, J=8.3 Hz, 1 H), 7.41-7.35
(m, 1 H), 7.23-7.18 (m, 1 H), 6.95 (d, J=1.6 Hz, 1 H), 6.48 (s, 2
H), 3.52-3.45 (m, 1H), 2.98-2.85 (m, 2 H), 1.91-1.79 (m, 2 H),
1.03-0.98 (m, 9 H); .sup.13C NMR (75 MHz, DMSO-d.sub.6) .delta.
154.5, 152.0, 144.9, 132.6, 126.8, 126.1, 124.2, 121.2, 120.9,
115.0, 51.2, 28.2, 21.1, 20.6, 14.3; MS (APCI) m/z 284 (M+H).sup.+;
Anal. Calcd for C.sub.16H.sub.21N.sub.5: C, 67.82; H, 7.47; N,
24.71; Found: C, 67.66; H, 7.39; N, 24.66.
Example 17
N.sup.1-Isopropyl-2-propyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-1-
,4-diamine
[0883] 79
[0884] Part A
[0885] A solution of
N.sup.1-isopropyl-2-propyl-1H-imidazo[4,5-c]quinoline- -1,4-diamine
(0.59 g, 2.1 mmol) in 15 mL of trifluoroacetic acid was treated
with platinum(IV) oxide (0.55 g, 2.4 mmol) and shaken under an
atmosphere of hydrogen (3.8.times.10.sup.5 Pa). After 6 days, the
reaction mixture was filtered through a pad of CELITE filter agent
and rinsed with a mixture of 85:15:0.1 CHCl.sub.3:MeOH:TFA until
the filtrate ran clear. The filtrate was concentrated under reduced
pressure to yield a white foam. The material was suspended in water
and treated with 50% NaOH solution until the pH reached 13. A white
solid precipitated and was triturated in the basic mixture for 1 h.
The white solid was collected by vacuum filtration. The solid was
purified by chromatography (SiO.sub.2, 95:5:0.1
CHCl.sub.3:MeOH:NH.sub.4OH) to yield 0.23 g of
N-isopropyl-2-propyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-1,4-di-
amine as a white solid.
[0886] mp 162-164.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 6.34 (s, 1H), 5.64 (s, 2 H), 3.38-3.23 (m, 2 H), 2.85-2.79
(m, 3 H), 2.78-2.71 (m, 2 H), 1.84-1.71 (m, 6 H), 0.99-0.86 (m, 9
H); .sup.13C NMR (75 MHz, DMSO-d.sub.6) .delta. 154.4, 149.3,
146.1, 137.9, 122.8, 105.7, 52.4, 32.5, 28.4, 23.3, 23.1, 22.9,
21.0, 20.7, 14.3; MS (APCI) m/z 288 (M+H).sup.+; Anal. Calcd for
C.sub.16H.sub.25N.sub.5: C, 66.87; H, 8.77; N, 24.37; Found: C,
66.65; H, 8.90; N, 24.08.
Example 18
N.sup.1-Isopropyl-1H-imidazo[4,5-c]quinoline-1,4-diamine
[0887] 80
[0888] Part A
[0889] A suspension of N'-(3-aminoquinolin-4-yl)hydrazine
tert-butyl carboxylate (6.50 g, 23.7 mmol) in 100 mL of toluene was
treated with triethyl orthoformate (8.68 mL, 52.2 mmol) and
pyridine hydrochloride (0.14 g, 1.2 mmol) and heated to 130.degree.
C. under an atmosphere of nitrogen. After 23 h, the reaction
mixture was concentrated under reduced pressure to yield a
red/brown oil. The oil was dissolved in CHCl.sub.3 (150 mL) and
washed with water (2.times.50 mL), brine (50 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to yield 6.74 of tert-butyl
N-(1H-imidazo[4,5-c]quinolin-1-yl)carbamate as a red/orange
oil.
[0890] Part B
[0891] A solution of tert-butyl
N-(1H-imidazo[4,5-c]quinolin-1-yl)carbamat- e (6.74 g, 23.7 mmol)
in 40 mL of ethanol was treated with 40 mL of HCl (40 mL, 119 mmol,
3 M in ethanol) and heated to reflux. After 1 h, the reaction
mixture was cooled to ambient temperature, diluted with 80 mL of
diethyl ether, and cooled in an ice water bath which precipitated a
tan solid. The HCl salt of the product was collected by vacuum
filtration and rinsed with diethyl ether until the filtrate ran
clear. The dried HCl salt was dissolved in 75 mL of water and made
basic by addition of 50% NaOH solution until the pH of the water
was 12-13. The free base of the product precipitated out and was
triturated in the basic water for 30 min while being cooled in an
ice water bath. The solid was collected by vacuum filtration and
dried under vacuum to give 2.86 g of
1H-imidazo[4,5-c]quinolin-1-amine as a tan granular solid.
[0892] Part C
[0893] A solution of 1H-imidazo[4,5-c]quinolin-1-amine (2.86 g,
15.5 mmol) in 60 mL of acetonitrile and 15 mL of glacial acetic
acid was treated with 2,2-dimethoxypropane (9.53 mL, 77.5 mmol) and
heated to 100.degree. C. under an atmosphere of nitrogen. After 18
h, the reaction mixture was concentrated under reduced pressure to
give a brown oil. The oil was dissolved in 100 mL of CHCl.sub.3 and
washed with 5% Na.sub.2CO.sub.3 solution (2.times.30 mL), water (30
mL) and brine (30 mL). The organic portion was dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to yield 3.48 g of N-(1H-imidazo[4,5-c]quinolin-1-yl)iso-
propylidenearnine as a brown oil.
[0894] Part D
[0895] A solution of
N-(1H-imidazo[4,5-c]quinolin-1-yl)isopropylideneamine (3.48 g, 15.5
mmol) in 75 mL of methanol was cooled in an ice water bath. The
solution was treated over 5 min with sodium borohydride (2.94 g,
77.6 mmol). After 1 h, the reaction mixture was quenched with 20 mL
of saturated NH.sub.4Cl solution and then concentrated under
reduced pressure to yield a brown soild. The solid was partitioned
between 80 mL CHCl.sub.3 and 20 mL saturated NaHCO.sub.3 solution
and the phases were separated. The organic portion was washed with
water (20 mL), brine (20 mL), dried over Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure to give a brown solid. The
solid was purified by chromatography (SiO.sub.2, 95:5:0.5
CHCl.sub.3:MeOH:NH.sub.4OH) to give 1.28 g of
N-(1H-imidazo[4,5-c]quinolin-1-yl)isopropylamine as a tan foam.
[0896] Part E
[0897] A solution of
N-(1H-imidazo[4,5-c]quinolin-1-yl)isopropylamine (1.36 g, 5.66
mmol) in 50 mL of chloroform was cooled in a cold water bath. The
solution was treated with MCPBA (2.03 g, 7.07 mmol) over 5 min and
then allowed to warm to ambient temperature. After 1 h, TLC showed
complete conversion to the intermediate 5-N-oxide. The reaction
mixture was again cooled with a cold water bath. The solution was
treated with concentrated ammonium hydroxide solution (25 mL, 30%)
and stirred rapidly to homogenize. The reaction mixture was treated
with p-toluenesulfonyl chloride (1.13 g, 5.94 g) over 5 min and
allowed to warm to ambient temperature. After 30 min, the reaction
mixture was diluted with 50 mL of CHCl.sub.3 and 25 mL of water. An
undissolved solid between the phases was filtered off, saved, and
the phases were separated. The organic portion was washed with
saturated NaHCO.sub.3 solution (30 mL), water (30 mL) and brine (30
mL). The organic portion was then dried over Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure to yield a
tan/orange solid. A high-performance liquid chromatography (HPLC)
analysis of the filtered solid matched that of the solid from the
concentrated organic extracts. The combined solid was
recrystallized twice from MeOH to give 1.18 g of
N.sup.1-isopropyl-1H-imidazo[4,5-c]quin- oline-1,4-diamine as an
off-white solid.
[0898] mp dec. >250.degree. C.; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 8.61 (dd, J=8.1, 1.1 Hz, 1 H), 8.23 (s, 1 H),
7.56 (d, J=7.6 Hz, 1 H), 7.43-7.37 (m, 1 H), 7.23-7.18 (m, 1 H),
7.04 (d, J=3.4 Hz, 1 H), 6.58 (s, 2 H), 3.57-3.47 (m, 1 H), 1.03
(d, J=6.2 Hz, 6 H); .sup.13C NMR (75 MHz, DMSO-d.sub.6) .delta.
152.4, 145.3, 132.3, 127.3, 126.0, 125.1, 121.5, 121.0, 115.1,
52.6, 20.6; MS (APCI) m/z 242 (M+H).sup.+; Anal. Calcd for
C.sub.13H.sub.15N.sub.5: C, 64.71; H, 6.27; N, 29.02; Found: C,
63.11; H, 6.30; N, 27.96.
Example 19
N.sup.1-Isopropyl-2-propyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinoline-1,4-
-diamine
[0899] 81
[0900] Part A
[0901] A suspension of 7-bromo-4-chloro-3-nitroquinoline (75.00 g,
260.9 mmol) in 350 mL of dichloromethane was cooled to 0.degree. C.
under an atmosphere of nitrogen. The suspension was treated with
triethylamine (43.25 mL, 326.1 mmol), which dissolved most of the
material. A solution of tert-butyl carbazate (37.93 g, 287.0 mmol)
in 250 mL of dichloromethane was added to the reaction mixture over
20 min. The reaction was allowed to slowly come to ambient
temperature. After 15 h, the reaction mixture was washed with 5%
Na.sub.2CO.sub.3 solution (2.times.100 mL) and water (100 mL). The
combined aqueous washes were back-extracted with CHCl.sub.3 (50
mL). The combined organic portions were washed with brine (100 mL),
dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure to yield 99.98 g of
N'-(7-bromo-3-nitroquinolin-4-yl)hydrazine tert-butyl carboxylate
as a dark red solid.
[0902] Part B
[0903] A suspension of N'-(7-bromo-3-nitroquinolin-4-yl)hydrazine
tert-butyl carboxylate (50.0 g, 131 mmol) in 320 mL of acetonitrile
(MeCN) and 80 mL of methanol was treated with platinum on carbon
(5.0 g, 1.3 mmol, 5% w/w) and shaken under an atmosphere of
hydrogen (3.8.times.10.sup.5 Pa). After 4 h, the reaction mixture
was filtered through a pad of CELITE filter agent and rinsed with
portions of MeCN:MeOH (1:1) until the filtrate ran clear. The
filtrate was concentrated under reduced pressure to yield 37.1 g of
N'-(3-amino-7-bromoquinolin-4-yl)hydrazine tert-butyl carboxylate
as a tan solid.
[0904] Part C
[0905] A solution of N'-(3-amino-7-bromoquinolin-4-yl)hydrazine
tert-butyl carboxylate (37.1 g, 105 mmol) in 315 mL of toluene was
treated with trimethyl orthobutyrate (16.7 mL, 105 mmol) and
pyridine hydrochloride (0.12 g, 1.05 mmol). The reaction mixture
was heated to reflux under an atmosphere of nitrogen. After 4 h,
the reaction mixture was cooled to ambient temperature and
concentrated under reduced pressure to give a brown oil. The oil
was dissolved in 300 mL of CHCl.sub.3. The solution was washed with
5% Na.sub.2CO.sub.3 (100 mL), water (100 mL) and brine (100 mL).
The organic portion was dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to yield a brown foam. The foam
was purified by chromatography (SiO.sub.2, 100:0 gradient to 95:5
CHCl.sub.3:MeOH) to yield 30.1 g of
(7-bromo-2-propyl-1H-imidazo[4,5-c]qu- inolin-1-yl) tert-butyl
carbamate as a light brown solid.
[0906] Part D
[0907] A suspension of
(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl) tert-butyl
carbamate (30.1 g, 74.3 mmol) in 25 mL of ethanol was treated with
HCl in ethanol (86.4 mL, 37.1 mmol, 4.3 M) and heated to
100.degree. C. After 30 min, the reaction mixture was cooled to
ambient temperature and concentrated under reduced pressure to
yield a brown solid. The solid was suspended in 100 mL of water,
stirred vigorously and treated with 50% NaOH solution until the pH
of the liquid rose to 12-13. A brown solid collected around the
stir bar. The water was diluted with 200 mL of dichloromethane and
the solid was broken apart. The material was triturated in the
biphasic mixture overnight. After triturating for 15 h, the mixture
was filtered to give the crude free base as a light brown solid.
The solid was dried under vacuum to give 17.6 g of
7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-amine as a light brown
solid.
[0908] Part E
[0909] A suspension of
7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-amine (17.6 g, 57.7
mmol) in 160 mL of acetonitrile and 40 mL of glacial acetic acid
was treated with 2,2-dimethoxypropane (35.5 mL, 288 mmol). The
reaction mixture was heated to 100.degree. C. under an atmosphere
of nitrogen. After 16 h, the reaction was cooled to ambient
temperature and concentrated under reduced pressure to yield a
brown oil. The oil was dissolved in CHCl.sub.3 (200 mL). The
CHCl.sub.3 solution was washed with saturated NaHCO.sub.3 solution
(2.times.50 mL), water (50 mL) and brine (50 mL). The organic
portion was then dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to yield 18.4 g of
N-(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)isopropylideneamine
as a red/brown foam.
[0910] Part F
[0911] A solution of
N-(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)is-
opropylideneamine (18.4 g, 53.3 mmol) in 100 mL of methanol was
placed under an atmosphere of nitrogen and cooled in an ice water
bath. The solution was treated with sodium borohydride (2.32 g,
61.3 mmol) over 30 min. The reaction mixture was allowed to slowly
come to ambient temperature. After 1.5 h, the reaction was quenched
by the addition of 25 mL of saturated NH.sub.4Cl solution. The
reaction mixture was concentrated under reduced pressure to remove
the methanol. The residue was partitioned between chloroform (150
mL) and 10% Na.sub.2CO.sub.3 solution (35 mL), and the phases were
separated. The organic portion was washed with another portion of
10% Na.sub.2CO.sub.3 solution (35 mL), water (35 mL) and brine (35
mL). The organic portion was dried over Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure to yield a brown foam. The
foam was purified by chromatography (SiO.sub.2, 97:3
CHCl.sub.3:MeOH gradient to 9:1) to give 16.3 g of
N-(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)isopropylamine
as a dark tan solid.
[0912] Part G
[0913] A solution of
N-(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)is- opropylamine
(9.10 g, 26.2 mmol) in 200 mL of chloroform was placed under an
atmosphere of nitrogen and cooled in an ice water bath. The
solution was treated with MCPBA (8.28 g, 28.8 mmol, 77% max) and
allowed to slowly come to ambient temperature. After 2 h, LC/MS and
HPLC indicated complete conversion to the 5-N-oxide intermediate.
The reaction mixture was again cooled in an ice water bath. The
reaction mixture was treated with ammonium hydroxide solution (50
mL, 30%) and stirred vigorously. The mixture was treated with
p-toluenesulfonyl chloride (5.24 g, 27.5 mmol) and allowed to come
to ambient temperature. After 30 min, the reaction was diluted with
50 mL of water, and the phases were separated. The organic portion
was washed with water (75 mL), brine (75 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to yield a light brown solid. The solid was purified by
chromatography (SiO.sub.2, 95:5 CHCl.sub.3:MeOH) and then
recrystallized from acetonitrile to give 4.52 g of
7-bromo-N.sup.1-isopropyl-2-propyl-1H-imid-
azo[4,5-c]quinoline-1,4-diamine as off white crystals. mp
226-228.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
8.44 (d, J=8.7 Hz, 1 H), 7.71 (d, J=2.1 Hz, 1 H), 7.36 (dd, J=8.7,
2.1 Hz, 1 H), 6.99 (d, J=1.7 Hz, 1 H), 6.73 (s, 2 H), 3.53-3.40 (m,
1H), 2.90 (s, 2 H), 1.93-1.80 (m, 2 H), 1.05-1.00 (m, 9 H);
.sup.13C NMR (125 MHz, DMSO-d.sub.6) .delta. 154.9, 152.9, 146.3,
132.5, 127.8, 124.2, 123.5, 123.1, 119.7, 114.0, 79.5, 51.4, 28.2,
21.1, 20.6, 14.3; MS (APCI) m/z 362, 364 (M+H).sup.+; Anal. Calcd
for C.sub.16H.sub.20BrN.sub.5.multidot.0.25H.sub.2O: C, 52.40; H,
5.63; N, 19.09; Found: C, 52.03; H, 5.42; N, 19.14.
[0914] Part H
[0915] A suspension of
7-bromo-N.sup.1-isopropyl-2-propyl-1H-imidazo[4,5-c-
]quinoline-1,4-diamine (1.00 g, 2.76 mmol) in 20 mL of 1-propanol
was treated with pyridine-3-boronic acid 1,3-propane diol cyclic
ester (0.540 g, 3.31 mmol). The head-space of the reaction flask
was purged and back-filled with nitrogen (3.times.). The reaction
mixture was then treated with triphenylphosphine (11 mg, 0.041
mmol), sodium carbonate (1.66 mL, 3.31 mmol, 2 M solution in
water), water (2 mL) and palladium(II) acetate (3.1 mg, 0.014
mmol). Again the head-space of the reaction flask was purged and
back-filled with nitrogen (3.times.). The reaction was heated to
100.degree. C. After 17 h, the reaction was cooled to ambient
temperature and concentrated under reduced pressure to yield a
brown solid. The solid was dissolved and partitioned between 15 mL
of water and 15 mL of chloroform and then separated. The aqueous
portion was extracted with chloroform (2.times.15 mL). The combined
organic extracts were washed with brine (15 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to yield a tan solid. The solid was purified by chromatography
(SiO.sub.2, 95:5 CHCl.sub.3:MeOH) and recrystallized from
acetonitrile to give 0.515 g of
N.sup.1-isopropyl-2-propyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinoline-1,-
4-diamine as white crystals.
[0916] mp 218-219.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 8.99 (d, J=1.7 Hz, 1 H), 8.60-8.57 (m, 2 H), 8.19-8.16 (m,
1H), 7.88 (d, J=1.9 Hz, 1H), 7.61 (dd, J=8.5, 1.9 Hz, 1 H),
7.53-7.49 (m, 1 H), 7.04 (s, 1 H), 6.59 (s, 2 H), 3.57-3.49 (m, 1
H), 2.92-2.87 (m, 2 H), 1.94-1.82 (m, 2 H), 1.06-1.01 (m, 9 H);
.sup.13C NMR (75 MHz, DMSO-d.sub.6) .delta. 154.8, 152.5, 148.6,
148.1, 145.4, 136.2, 135.4, 134.5, 132.5, 124.5, 124.3, 123.9,
122.2, 119.6, 114.7, 51.3, 28.2, 21.1, 20.6; MS (APCI) m/z 361
(M+H).sup.+; Anal. Calcd for C.sub.21H.sub.24N.sub.6: C, 69.97; H,
6.71; N, 23.31; Found: C, 69.78; H, 6.55; N, 23.51.
Example 20
7-Benzyloxy-2-ethoxymethyl-N.sup.1-isopropyl-1H-imidazo[4,5-c]quinoline-1,-
4-diamine
[0917] 82
[0918] Part A
[0919] A mixture of triethyl orthoformate (92 mL, 0.55 mol) and
2,2-dimethyl-1,3-dioxane-4,6-dione (75.3 g, 0.522 mol) (Meldrum's
acid) was heated at 55.degree. C. for 90 minutes and then cooled to
45.degree. C. A solution of 3-benzyloxyaniline (100.2 g, 0.5029
mol) in methanol (200 mL) was slowly added to the reaction over a
period 45 minutes while maintaining the reaction temperature below
50.degree. C. The reaction was then heated at 45.degree. C. for one
hour, allowed to cool to room temperature, and stirred overnight.
The reaction mixture was cooled to 1.degree. C., and the product
was isolated by filtration and washed with cold ethanol (.about.400
mL) until the filtrate was colorless.
5-{[(3-Benzyloxy)phenylimino]methyl}-2,2-dimethyl-1,3-dioxane-4,6-dione
(170.65 g) was isolated as a tan, powdery solid.
[0920] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.21 (d, J=14.2
Hz, 1H), 8.61 (d, J=14.2 Hz, 1H), 7.49-7.30 (m, 7H), 7.12 (dd,
J=8.1, 1.96 Hz, 1H), 6.91 (dd, J=8.4, 2.1 Hz, 1H), 5.16 (s, 2H),
1.68 (s, 6H).
[0921] Part B
[0922] A mixture of
5-{[(3-benzyloxy)phenylimino]methyl}-2,2-dimethyl-1,3--
dioxane-4,6-dione (170.65 g, 0.483 mol) and DOWTHERM A heat
transfer fluid (800 mL) was heated to 100.degree. C. and then
slowly added to a flask containing DOWTHERM A heat transfer fluid
(1.3 L, heated at 210.degree. C.) over a period of 40 minutes.
During the addition, the reaction temperature was not allowed to
fall below 207.degree. C. Following the addition, the reaction was
stirred at 210.degree. C. for one hour, and then allowed to cool to
ambient temperature. A precipitate formed, which was isolated by
filtration, washed with diethyl ether (1.7 L) and acetone (0.5 L),
and dried in an oven to provide 76.5 g of 7-benzyloxyquinolin-4-ol
as a tan powder.
[0923] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.53 (s, 1H),
7.99 (dd, J=7.4, 2.4 Hz, 1H), 7.79 (d, J=7.4 Hz, 1H), 7.50-7.32 (m,
5H), 7.00 (s, 1H), 6.98 (dd, J=7.4, 2.5 Hz, 1H), 5.93 (d, J=7.5 Hz,
1H), 5.20 (s, 2H).
[0924] Part C
[0925] A mixture of 7-benzyloxyquinolin-4-ol (71.47 g, 0.2844 mol)
and propionic acid (700 mL) was heated to 125.degree. C. with
vigorous stirring. Nitric acid (23.11 mL of 16 M) was slowly added
over a period of 30 minutes while maintaining the reaction
temperature between 121.degree. C. and 125.degree. C. After the
addition, the reaction was stirred at 125.degree. C. for 1 hour
then allowed to cool to ambient temperature. The resulting solid
was isolated by filtration, washed with water, and dried in an oven
for 1.5 days to provide 69.13 g of 7-benzyloxy-3-nitroquinolin-4-ol
as a grayish powder.
[0926] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 12.77 (s, 1H),
9.12 (s, 1H), 8.17 (dd, J=6.3, 3.3 Hz, 1H), 7.51-7.33 (m, 5H),
7.21-7.17 (m, 2H), 5.25 (s, 2H).
[0927] Part D
[0928] A suspension of 7-benzyloxy-3-nitroquinolin-4-ol (75.0 g,
253 mmol), which was made in a separate run, in 500 mL of
N,N-dimethylformamide was placed under an atmosphere of nitrogen.
The suspension was treated with phosphorous oxychloride (27.8 mL,
304 mmol) dropwise over 1.5 h. After 18 h, the reaction mixture was
cooled to 0.degree. C. and then poured into 1 L of ice water. The
mixture was stirred until the ice had melted. A tan/yellow
precipitate was collected by vacuum filtration. The solid was
dissolved in dichloromethane (500 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure to yield 71.7 g of
7-benzyloxy-4-chloro-3-nitro-quinoline as an orange solid.
[0929] Part E
[0930] A solution of tert-butyl carbazate (33.1 g, 251 mmol) in 150
mL of dichloromethane was treated with triethylamine (66.5 mL, 502
mmol). The solution was placed under an atmosphere of nitrogen and
cooled in a cold-water bath. The solution was treated with a
solution of 7-benzyloxy-4-chloro-3-nitroquinoline (71.7 g, 228
mmol) in 350 mL of dichloromethane over 1 h. The reaction was
stirred and allowed to warm to ambient temperature. After 15 h, the
reaction was diluted with 200 mL of water and 250 mL of CHCl.sub.3
and the phases were separated. The organic portion was washed with
water (200 mL), brine (200 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure to yield an orange
solid. The solid was recrystallized from dichloromethane to yield
53.5 g of N'-(7-benzyloxy-3-nitroquinolin-4-yl)hydrazine tert-butyl
carboxylate as yellow crystals.
[0931] Part F
[0932] A solution of N'-(7-benzyloxy-3-nitroquinolin-4-yl)hydrazine
tert-butyl carboxylate (20.00 g, 48.73 mmol) in 200 mL of methanol
and 200 mL of acetonitrile was treated with platinum on carbon
(2.00 g, 0.51 mmol) and shaken under an atmosphere of hydrogen
(3.8.times.10.sup.5 Pa). After 17 h, the mixture was filtered
through a pad of CELITE filter agent and rinsed with MeOH:MeCN
(1:1) until the filtrate ran clear. The filtrate was concentrated
under reduced pressure to yield 18.21 g of
N'-(3-amino-7-benzyloxyquinolin-4-yl)hydrazine tert-butyl
carboxylate as a red/orange solid.
[0933] Part G
[0934] A suspension of
N'-(3-amino-7-benzyloxyquinolin-4-yl)hydrazine tert-butyl
carboxylate (29.6 g, 77.8 mmol) in 250 mL of 1,2-dichloroethane was
placed under an atmosphere of nitrogen. The mixture was treated
with triethylamine (30.9 mL, 233 mmol). The mixture was then
treated dropwise with ethoxyacetyl chloride (10.5 g, 85.6 mmol).
After 2 h, the reaction was concentrated under reduced pressure to
give a brown oil. The oil was dissolved in 200 mL of 1-butanol and
treated with pyridinium p-toluenesulfonate (0.25 g, 1.0 mmol). The
mixture was heated to 135.degree. C. under an atmosphere of
nitrogen. After 20 h, the reaction mixture was cooled to ambient
temperature and concentrated under reduced pressure to give a brown
oil. The oil was dissolved in 250 mL of CHCl.sub.3 and washed with
saturated NaHCO.sub.3 solution (75 mL), water (75 mL) and brine (75
mL). The organic portion was then dried over Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure to give an
orange/brown oil. The oil was purified by chromatography
(SiO.sub.2, 9:1 CHCl.sub.3:MeOH) to yield 14.4 g of
(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)tert-butyl
carbamate as an orange/brown foam.
[0935] Part H
[0936] A suspension of
(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinol-
in-1-yl)tert-butyl carbamate (14.4 g, 32.1 mmol) in 100 mL of
ethanol was treated with HCl in ethanol (38 mL, 160 mmol, 4.3 M).
The mixture was heated to 100.degree. C. under an atmosphere of
nitrogen. After 2 h, the reaction mixture was cooled to ambient
temperature at which point a solid precipitated from solution. The
mixture was diluted with 100 mL of diethyl ether and the solid was
triturated for 15 min. The solid was collected by vacuum filtration
and washed with several portions of diethyl ether. The solid was
dried under vacuum for 2 h. The dry solid was suspended in 150 mL
of water and treated with 50% NaOH solution until the pH of the
liquid was 12. A brown solid precipitated. The mixture was diluted
with 200 mL of CH.sub.2Cl.sub.2 and stirred until the solid
dissolved. The layers were then separated. The aqueous portion was
extracted with CH.sub.2Cl.sub.2 (2.times.100 mL). The combined
organic extracts were washed with brine (100 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to yield 6.91 g of
7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-amine as a
dark tan solid.
[0937] Part I
[0938] A suspension of
7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinoli- n-1-amine
(6.91 g, 19.8 mmol) in 55 mL of acetonitrile was treated with
2,2-dimethoxypropane (12.2 mL, 99.2 mmol) and 14 mL of glacial
acetic acid. The reaction mixture was heated to 100.degree. C.
under an atmosphere of nitrogen. After 22 h, the reaction was
cooled to ambient temperature and concentrated under reduced
pressure to yield a brown oil. The oil was dissolved in 125 mL of
CHCl.sub.3 and washed with saturated NaHCO.sub.3 solution
(2.times.30 mL) and water (30 mL). The combined aqueous washes were
back-extracted with CHCl.sub.3 (25 mL). The combined organic
extracts were washed with brine (50 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to yield 7.69 g of
N-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-
-yl)isopropylideneamine as a brown solid.
[0939] Part J
[0940] A solution of
N-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinol-
in-1-yl)isopropylideneamine (7.69 g, 19.8 mmol) in 50 mL of
methanol was cooled to 0.degree. C. The solution was treated with
sodium borohydride (1.12 g, 29.7 mmol) over 10 min. The reaction
was allowed to slowly come to ambient temperature. After 2 h, the
reaction was quenched with 15 mL of saturated NH.sub.4Cl solution
and concentrated under reduced pressure to yield a tan solid
residue. The solid was dissolved in 100 mL of CHCl.sub.3 and 25 mL
of saturated K.sub.2CO.sub.3 solution then separated. The organic
portion was washed with water (25 mL), brine (25 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated to yield a brown oil.
The oil was purified by chromatography (SiO.sub.2, 98:2
CHCl.sub.3:MeOH) to yield 6.63 g of
N-(7-benzyloxy-2-ethoxymethyl-H-imida-
zo[4,5-c]quinolin-1-yl)isopropylamine as a tan foam.
[0941] Part K
[0942] A solution of
N-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinol-
in-1-yl)isopropylamine (6.63 g, 17.0 mmol) in 90 mL of CHCl.sub.3
was treated with MPCBA (6.29 g, 25.5 mmol, 70%). After 3 h, HPLC
and LC/MS indicated complete conversion to the intermediate
5-N-oxide. The reaction mixture was then treated with concentrated
ammonium hydroxide solution (30 mL, 30%). The biphasic reaction
mixture was stirred vigorously while p-toluenesulfonyl chloride
(3.40 g, 17.9 mmol) was added. After 45 min, LC/MS indicated
complete conversion to the 4-amine. The reaction mixture was
diluted with 30 mL of water and 45 mL of CHCl.sub.3 and separated.
The organic portion was washed with 10% Na.sub.2CO.sub.3 solution
(50 mL) and water (50 mL). The combined aqueous portions were then
back-extracted with CHCl.sub.3 (25 mL). The combined organic
portions were washed with brine (50 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated to yield a tan solid.
The solid was purified by chromatography (SiO.sub.2, 96:4
CHCl.sub.3:MeOH) to give 5.90 g of
7-benzyloxy-2-ethoxymethyl-N.sup.-
1-isopropyl-1H-imidazo[4,5-c]quinoline-1,4-diamine as a light tan
solid.
[0943] mp 194-196.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 8.47 (d, J=8.9 Hz, 1H), 7.50-7.48 (m, 2 H), 7.43-7.38 (m, 2
H), 7.35-7.30 (m, 1 H), 7.09 (d, J=2.6 Hz, 1 H), 6.96 (dd, J=9.0,
2.5 Hz, 1 H), 6.91 (d, J=1.5 Hz, 1 H), 6.57 (s, 2 H), 5.20 (s, 2
H), 4.72 (s, 2 H), 3.64-3.57 (m, 3 H), 1.15 (t, J=7.0 Hz, 3 H),
1.01 (d, J=6.1 Hz, 6 H); .sup.13C NMR (75 MHz, DMSO-d.sub.6)
.delta. 157.9, 152.6, 149.4, 147.1, 137.7, 133.7, 128.8, 128.1,
128.0, 122.7, 111.8, 109.2, 108.4, 69.5, 65.8, 63.0, 51.6, 20.6,
15.3; MS (APCI) m/z 406 (M+H).sup.+; Anal. Calcd for
C.sub.23H.sub.27N.sub.5O.sub.2: C, 68.13; H, 6.71; N, 17.27; Found:
C, 68.15; H, 6.91; N, 17.24.
Example 21
4-Amino-2-ethoxymethyl-1-isopropylamino-1H-imidazo[4,5-c]quinolin-7-ol
[0944] 83
[0945] Part A
[0946] A solution of
7-benzyloxy-2-ethoxymethyl-N-isopropyl-1H-imidazo[4,5-
-c]quinoline-1,4-diamine (1.67 g, 4.12 mmol) in 25 mL of toluene
and 25 mL of methanol was treated with palladium on carbon (0.44 g,
0.42 mmol, 10% w/w). The mixture was shaken under an atmosphere of
hydrogen (3.8.times.10.sup.5 Pa). After 16 h, the reaction was
filtered through a pad of CELITE filter agent and rinsed with
solvent until the filtrate ran clear. The filtrate was concentrated
under reduced pressure to provide a white solid. Purification by
chromatography (SiO.sub.2, 3:1 CHCl.sub.3: (80:18:2
CHCl.sub.3:MeOH:NH.sub.4OH) gradient to 1:1) gave 0.50 g of
4-amino-2-ethoxymethyl-1-isopropylamino-1H-imidazo[4,5-c]quinolin-7-ol
as a white solid. MS (APCI) m/z 316 (M+H).sup.+.
Example 22
[3-(4-Amino-2-ethoxymethyl-1-isopropylamino-1H-imidazo[4,5-c]quinolin-7-yl-
oxy)propyl] tert-butyl carbamate
[0947] 84
[0948] Part A
[0949] A solution of di-tert-butyl dicarbonate (19.05 g, 87.29
mmol) in tetrahydrofuran (20 mL) was added dropwise to a mixture of
3-amino-1-propanol (6.55 g, 87.2 mmol), tetrahydrofuran (50 mL),
and 10% aqueous sodium hydroxide (35 mL). The reaction was stirred
for 16 hours. The tetrahydrofuiran was removed under reduced
pressure, and the residue was adjusted to pH 3 with the slow
addition of 15% aqueous potassium hydrogen sulfate. The mixture was
extracted with ethyl acetate (3.times.), and the combined organic
fractions were washed sequentially with water and brine, dried over
anhydrous magnesium sulfate, filtered, and concentrated under
reduced pressure to provide 16.6 g of tert-butyl
3-hydroxypropylcarbamate as a colorless oil containing some
residual ethyl acetate.
[0950] Part B
[0951] Iodine (21.1 g, 83.1 mmol) was added in three portions to a
solution of triphenylphosphine (19.83 g, 75.6 mmol) and imidazole
(5.15 g, 75.6 mmol) in dichloromethane (300 mL). The resulting
reddish-brown solution with a white precipitate was stirred until
all of the iodine had dissolved. A solution of tert-butyl
3-hydroxypropylcarbamate (13.25 g, 75.61 mmol) in dichloromethane
(150 mL) was added over a period of 45 minutes, and the reaction
was stirred for 16 hours at ambient temperature. The reaction
mixture was poured into saturated aqueous sodium thiosulfate and
stirred until solution became colorless. The organic layer was
separated and washed sequentially with saturated aqueous sodium
thiosulfate, water, and brine; dried over anhydrous magnesium
sulfate; filtered; and concentrated under reduced pressure to a
pale yellow oil. The oil was purified by flash column
chromatography (eluting with 80:20 hexanes:ethyl acetate) to a pale
yellow oil which slowly crystallizes upon standing to afford 16.2 g
of tert-butyl 3-iodopropylcarbamate as a yellow solid.
[0952] Part C
[0953] A solution of
4-amino-2-ethoxymethyl-1-isopropylamino-1H-imidazo[4,-
5-c]quinolin-7-ol (0.11 g, 0.35 mmol) in 10 mL of
N,N-dimethylformamide was placed under an atmosphere of nitrogen
and was treated with cesium carbonate (0.23 g, 0.70 mmol). After 5
min of stirring the mixture was treated with tert-butyl
3-iodopropylcarbamate (0.12 g, 0.35 mmol) and heated to 65.degree.
C. After 60 h, the reaction mixture was cooled to ambient
temperature and then poured into 100 mL of ice water which resulted
in a cloudy suspension. The mixture was extracted with CHCl.sub.3
(5.times.25 mL). The combined organic extracts were then washed
with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to yield a tan oil.
Chromatography (95:5 CHCl.sub.3:(80:18:2
CHCl.sub.3:MeOH:NH.sub.4OH) gradient to 1:1 gave 0.040 g of
[3-(4-amino-2-ethoxymethyl-1-isopropylamino-1H-imidazo[4,-
5-c]quinolin-7-yloxy)propyl] tert-butyl carbamate as a light tan
solid. LC/MS (APCI) m/z 473 (M+H).sup.+.
Example 23
[3-(4-Amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-ylamino)propyl]morp-
holine-4-carboxamide
[0954] 85
[0955] A solution of
N.sup.1-(3-aminopropyl)-2-ethoxymethyl-1H-imidazo[4,5-
-c]quinoline-1,4-diamine (0.500 g, 1.59 mmol) in 10 mL of
CH.sub.2Cl.sub.2 was treated with triethylamine (0.443 mL, 3.34
mmol) under an atmosphere of nitrogen and cooled to 0.degree. C.
The reaction mixture was treated dropwise with 4-morpholinecarbonyl
chloride (0.065 mL, 0.835 mmol) and allowed to slowly come to
ambient temperature. After 60 h, the reaction mixture was quenched
with 10% Na.sub.2CO.sub.3 solution, diluted with CHCl.sub.3 and the
phases were separated. The organic portion was washed with water
and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure to yield a light yellow solid.
Chromatography (SiO.sub.2, 9:1 CHCl.sub.3:(80:18:2
CHCl.sub.3:MeOH:NH.sub.4OH) gradient to 1:1) gave a glassy solid.
The solid was triturated with diethyl ether and filtered to give
0.046 g of
[3-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-ylamino)propyl]mor-
pholine-4-carboxamide as a white solid.
[0956] mp 158-160.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 8.44 (d, J=7.9 Hz, 1H), 7.58 (d, J=8.1 Hz, 1 H), 7.46-7.41
(m, 1 H), 7.26-7.21 (m, 1 H), 6.96 (t, J=5.5 Hz, 1 H), 6.60 (s, 2
H), 6.53 (t, J=5.1 Hz, 1 H), 4.75 (s, 2 H), 3.61 (q, J=7.0 Hz, 2
H), 3.50 (t, J=4.7 Hz, 4 H), 3.22-3.15 (m, 8 H), 1.72 (p, J=6.9 Hz,
2 H), 1.17 (t, J=7.0 Hz, 3 H); .sup.13C NMR (75 MHz, DMSO-d.sub.6)
.delta. 158.0, 152.3, 149.5, 145.3, 132.4, 127.4, 126.1, 124.2,
121.2, 114.7, 66.3, 65.8, 63.1, 50.2, 44.1, 38.3, 28.5, 15.4; MS
(APCI) m/z 428 (M+H).sup.+; Anal. Calcd for
C.sub.21H.sub.29N.sub.7O.sub.3: C, 59.00; H, 6.84; N, 22.93; Found:
C, 58.76; H, 7.04; N, 22.82.
[0957] Exemplary Compounds
[0958] Certain exemplary compounds, including some of those
described above in the Examples, have the following Formula (I-1d)
and the following R.sub.1, R.sub.2, and R.sub.3 substituents,
wherein each line of the table represents a specific compound.
1 I-Id 86 R.sub.1 R.sub.2 R.sub.3 isopropyl hydrogen pyridin-3-yl
isopropyl hydrogen benzyloxy isopropyl hydrogen
2-methanesulfonylaminoethoxy isopropyl hydrogen
3-methanesulfonylaminopropoxy isopropyl hydrogen
2-(pyridin-3-yl)ethyl isopropyl methyl pyridin-3-yl isopropyl
methyl benzyloxy isopropyl methyl 2-methanesulfonylaminoethoxy
isopropyl methyl 3-methanesulfonylaminopropoxy isopropyl methyl
2-(pyndin-3-yl)ethyl isopropyl propyl pyridin-3-yl isopropyl propyl
benzyloxy isopropyl propyl 2-methanesulfonylaminoethoxy isopropyl
propyl 3-methanesulfonylaminopropoxy isopropyl propyl
2-(pyridin-3-yl)ethyl isopropyl butyl pyridin-3-yl isopropyl butyl
benzyloxy isopropyl butyl 2-methanesulfonylaminoet- hoxy isopropyl
butyl 3-methanesulfonylaminopropoxy isopropyl butyl
2-(pyridin-3-yl)ethyl isopropyl 2-methoxyethyl pyridin-3-yl
isopropyl 2-methoxyethyl benzyloxy isopropyl 2-methoxyethyl
2-methanesulfonylaminoethoxy isopropyl 2-methoxyethyl
3-methanesulfonylaminopropoxy isopropyl 2-methoxyethyl
2-(pyridin-3-yl)ethyl isopropyl ethoxymethyl pyridin-3-yl isopropyl
ethoxymethyl benzyloxy isopropyl ethoxymethyl
2-methanesulfonylaminoethoxy isopropyl ethoxymethyl
3-methanesulfonylaminopropoxy isopropyl ethoxymethyl
2-(pyridin-3-yl)ethyl benzyl hydrogen pyridin-3-yl benzyl hydrogen
benzyloxy benzyl hydrogen 2-methanesulfonylaminoethoxy benzyl
hydrogen 3-methanesulfonylaminopropoxy benzyl hydrogen
2-(pyridin-3-yl)ethyl benzyl methyl pyridin-3-yl benzyl methyl
benzyloxy benzyl methyl 2-methanesulfonylaminoethoxy benzyl methyl
3-methanesulfonylaminopropoxy benzyl methyl 2-(pyridin-3-yl)ethyl
benzyl propyl pyridin-3-yl benzyl propyl benzyloxy benzyl propyl
2-methanesulfonylaminoethoxy benzyl propyl
3-methanesulfonylaminopropoxy benzyl propyl 2-(pyridin-3-yl)ethyl
benzyl butyl pyridin-3-yl benzyl butyl benzyloxy benzyl butyl
2-methanesulfonylaminoethoxy benzyl butyl
3-methanesulfonylaminopropoxy benzyl butyl 2-(pyridin-3-yl)ethyl
benzyl 2-methoxyethyl pyridin-3-yl benzyl 2-methoxyethyl benzyloxy
benzyl 2-methoxyethyl 2-methanesulfonylaminoethoxy benzyl
2-methoxyethyl 3-methanesulfonylaminopropoxy benzyl 2-methoxyethyl
2-(pyridin-3 -yl)ethyl benzyl ethoxymethyl pyridin-3-yl benzyl
ethoxymethyl benzyloxy benzyl ethoxymethyl 2-methanesulfonylaminoe-
thoxy benzyl ethoxymethyl 3-methanesulfonylaminopropoxy benzyl
ethoxymethyl 2-(pyridin-3-yl)ethyl 3-phenylpropyl hydrogen
pyridin-3-yl 3-phenylpropyl hydrogen benzyloxy 3-phenylpropyl
hydrogen 2-methanesulfonylaminoethoxy 3-phenylpropyl hydrogen
3-methanesulfonylaminopropoxy 3-phenylpropyl hydrogen
2-(pyridin-3-yl)ethyl 3-phenylpropyl methyl pyridin-3-yl
3-phenylpropyl methyl benzyloxy 3-phenylpropyl methyl 2-methane
sulfonyl aminoethoxy 3-phenylpropyl methyl
3-methanesulfonylaminopropoxy 3-phenylpropyl methyl
2-(pyridin-3-yl)ethyl 3-phenylpropyl propyl pyridin-3-yl
3-phenylpropyl propyl benzyloxy 3-phenylpropyl propyl
2-methanesulfonylaminoethoxy 3-phenylpropyl propyl
3-methanesulfonylaminopropoxy 3-phenylpropyl propyl
2-(pyridin-3-yl)ethyl 3-phenylpropyl butyl pyridin-3-yl
3-phenylpropyl butyl benzyloxy 3-phenylpropyl butyl
2-methanesulfonylaminoethoxy 3-phenylpropyl butyl
3-methanesulfonylaminopropoxy 3-phenylpropyl butyl
2-(pyridin-3-yl)ethyl 3-phenylpropyl 2-methoxyethyl pyridin-3-yl
3-phenylproyl 2-methoxyethyl benzyloxy 3-phenylpropyl
2-methoxyethyl 2-methanesulfonylaminoethoxy 3-phenylpropyl
2-methoxyethyl 3-methanesulfonylaminopropoxy 3-phenylpropyl
2-methoxyethyl 2-(pyridin-3-yl)ethyl 3-phenylpropyl ethoxymethyl
pyridin-3-yl 3-phenylpropyl ethoxymethyl benzyloxy 3-phenylpropyl
ethoxymethyl 2-methanesulfonylaminoethoxy 3-phenylpropyl
ethoxymethyl 3-methanesulfonylaminopropoxy 3-phenylpropyl
ethoxymethyl 2-(pyridin-3-yl)ethyl 3-[3-(2-propyl)ureido]propyl
hydrogen pyridin-3-yl 3-[3-(2-propyl)ureido]propyl hydrogen
benzyloxy 3-[3-(2-propyl)ureido]propyl hydrogen
2-methanesulfonylaminoethoxy 3-[3-(2-propyl)ureido]propyl hydrogen
3-methanesulfonylaminopropoxy 3-[3-(2-propyl)ureido]propyl hydrogen
2-(pyridin-3-yl)ethyl 3-[3-(2-propyl)ureido]propyl methyl
pyridin-3-yl 3-[3-(2-propyl)ureido]propyl methyl benzyloxy
3-[3-(2-propyl)ureido]propyl methyl 2-methanesulfonylaminoethoxy
3-[3-(2-propyl)ureido]propyl methyl 3-methanesulfonylaminopropoxy
3-[3-(2-propyl)ureido]propyl methyl 2-(pyridin-3-yl)ethyl
3-[3-(2-propyl)ureido]propyl propyl pyridin-3-yl
3-[3-(2-propyl)ureido]propyl propyl benzyloxy
3-[3-(2-propyl)ureido]propyl propyl 2-methanesulfonylaminoethoxy
3-[3-(2-propyl)ureido]propyl propyl 3-methanesulfonylaminopropoxy
3-[3-(2-propyl)ureido]propyl propyl 2-(pyridin-3-yl)ethyl
3-[3-(2-propyl)ureido]propyl butyl pyridin-3-yl
3-[3-(2-propyl)ureido]propyl butyl benzyloxy
3-[3-(2-propyl)ureido]propyl butyl 2-methanesulfonylaminoethoxy
3-[3-(2-propyl)ureido]propyl butyl 3-methanesulfonylaminopropoxy
3-[3-(2-propyl)ureido]propyl butyl 2-(pyridin-3-yl)ethyl
3-[3-(2-propyl)ureido]propyl 2-methoxyethyl pyridin-3-yl
3-[3-(2-propyl)ureido]propyl 2-methoxyethyl benzyloxy
3-[3-(2-propyl)ureido]propyl 2-methoxyethyl
2-methanesulfonylaminoethoxy 3-[3-(2-propyl)ureido]propyl
2-methoxyethyl 3-methanesulfonylaminopropoxy
3-[3-(2-propyl)ureido]propyl 2-methoxyethyl 2-(pyridin-3-yl)ethyl
3-[3-(2-propyl)ureido]propyl ethoxymethyl pyridin-3-yl
3-[3-(2-propyl)ureido]propyl ethoxymethyl benzyloxy
3-[3-(2-propyl)ureido]propyl ethoxymethyl
2-methanesulfonylaminoethoxy 3-[3-(2-propyl)ureido]propyl
ethoxymethyl 3-methanesulfonylaminopropoxy 3-[3-(2-propyl)ureido]p-
ropyl ethoxymethyl 2-(pyridin-3-yl-ethyl
3-methanesulfonylaminoprop- yl hydrogen pyridin-3-yl
3-methanesulfonylaminopropyl hydrogen benzyloxy
3-methanesulfonylaminopropyl hydrogen 2-methanesulfonylaminoethoxy
3-methanesulfonylaimnopropyl hydrogen 3-methanesulfonylaminopropoxy
3-methanesulfonylaminopropyl hydrogen 2-(pyridin-3-yl)ethyl
3-methanesulfonylaminopropyl methyl pyridin-3-yl
3-methanesulfonylaminopropyl methyl benzyloxy
3-methanesulfonylaminopropyl methyl 2-methanesulfonylaminoethoxy
3-methanesulfonylaminopropyl methyl 3-methanesulfonylaminopropoxy
3-methanesulfonylaminopropyl methyl 2-(pyridin-3-yl)ethyl
3-methanesulfonylaminopropyl propyl pyridin-3-yl
3-methanesulfonylaminopropyl propyl benzyloxy
3-methanesulfonylaminopropyl propyl 2-methanesulfonylaminoethoxy
3-methanesulfonylaminopropyl propyl 3-methanesulfonylaminopropoxy
3-methanesulfonylaminopropyl propyl 2-(pyridin-3-yl)ethyl
3-methanesulfonylaminopropyl butyl pyridin-3-yl
3-methanesulfonylaminopropyl butyl benzyloxy
3-methanesulfonylaminopropyl butyl 2-methanesulfonylaminoethoxy
3-methanesulfonylaminopropyl butyl 3-methanesulfonylaminopropoxy
3-methanesulfonylaminopropyl butyl 2-(pyridin-3-yl)ethyl
3-methanesulfonylaminopropyl 2-methoxyethyl pyridin-3-yl
3-methanesulfonylaminopropyl 2-methoxyethyl benzyloxy
3-methanesulfonylaminopropyl 2-methoxyethyl
2-methanesulfonylaminoethoxy 3-methanesulfonylaminopropyl
2-methoxyethyl 3-methanesulfonylaminopropoxy
3-methanesulfonylaminopropyl 2-methoxyethyl 2-(pyridin-3-yl)ethyl
3-methanesulfonylaminopropyl ethoxymethyl pyridin-3-yl
3-methanesulfonylaminopropyl ethoxymethyl benzyloxy
3-methanesulfonylaminopropyl ethoxymethyl
2-methanesulfonylaminoethoxy 3-methanesulfonylaminopropyl
ethoxymethyl 3-methanesulfonylaminopropoxy 3-methanesulfonylaminop-
ropyl ethoxymethyl 2-(pyridin-3-yl)ethyl
[0959] Certain exemplary compounds, including some of those
described above in the Examples, have the following Formulas (Ii or
IIb) and the following R.sub.1 and R.sub.2 substituents, wherein
each line of the table is matched with Formula Ii or IIb to
represent a specific compound.
2 87 R.sub.1 R.sub.2 isopropyl hydrogen isopropyl methyl isopropyl
propyl isopropyl butyl isopropyl 2-methoxyethyl isopropyl
ethoxymethyl benzyl hydrogen benzyl methyl benzyl propyl benzyl
butyl benzyl 2-methoxyethyl benzyl ethoxymethyl 3-phenylpropyl
hydrogen 3-phenylpropyl methyl 3-phenylpropyl propyl 3-phenylpropyl
butyl 3-phenylpropyl 2-methoxyethyl 3-phenylpropyl ethoxymethyl
3-[3-(2-propyl)ureido]propyl hydrogen 3-[3-(2-propyl)ureido]propy-
l methyl 3-[3-(2-propyl)ureido]propyl propyl
3-[3-(2-propyl)ureido]propyl butyl 3-[3-(2-propyl)ureido]propyl
2-methoxyethyl 3-[3-(2-propyl)ureido]propyl ethoxymethyl
3-methanesulfonylaminopropyl hydrogen 3-methanesulfonylaminopropy-
l methyl 3-methanesulfonylaminopropyl propyl
3-methanesulfonylaminopropyl butyl 3-methanesulfonylaminopropyl
2-methoxyethyl 3-methanesulfonylaminopropyl ethoxymethyl
Cytokine Induction in Human Cells
[0960] Many compounds of the invention have been found to modulate
cytokine biosynthesis by inducing the production of interferon
.alpha. and/or tumor necrosis factor .alpha. in human cells when
tested using the method described below. Particular examples
include but are not limited to the compounds of Examples 1-18.
[0961] An in vitro human blood cell system is used to assess
cytokine induction. Activity is based on the measurement of
interferon and tumor necrosis factor (.alpha.) (IFN and TNF,
respectively) secreted into culture media as described by Testerman
et. al. in "Cytokine Induction by the Immunomodulators Imiquimod
and S-27609", Journal of Leukocyte Biology, 58, 365-372 (September,
1995).
[0962] Blood Cell Preparation for Culture:
[0963] Whole blood from healthy human donors is collected by
venipuncture into EDTA vacutainer tubes. Peripheral blood
mononuclear cells (PBMC) are separated from whole blood by density
gradient centrifugation using HISTOPAQUE-1077. Blood is diluted 1:1
with Dulbecco's Phosphate Buffered Saline (DPBS) or Hank's Balanced
Salts Solution (HBSS). The PBMC layer is collected and washed twice
with DPBS or HBSS and resuspended at 4.times.10.sup.6 cells/mL in
RPMI complete. The PBMC suspension is added to 48 well flat bottom
sterile tissue culture plates (Costar, Cambridge, Mass. or Becton
Dickinson Labware, Lincoln Park, N.J.) containing an equal volume
of RPMI complete media containing test compound.
[0964] Compound Preparation:
[0965] The compounds are solubilized in dimethyl sulfoxide (DMSO).
The DMSO concentration should not exceed a final concentration of
1% for addition to the culture wells. The compounds are generally
tested at concentrations ranging from 30-0.014 .mu.M.
[0966] Incubation:
[0967] The solution of test compound is added at 60 .mu.M to the
first well containing RPMI complete and serial 3 fold dilutions are
made in the wells. The PBMC suspension is then added to the wells
in an equal volume, bringing the test compound concentrations to
the desired range (30-0.014 .mu.M). The final concentration of PBMC
suspension is 2.times.10.sup.6 cells/mL. The plates are covered
with sterile plastic lids, mixed gently and then incubated for 18
to 24 hours at 37.degree. C. in a 5% carbon dioxide atmosphere.
[0968] Separation:
[0969] Following incubation the plates are centrifuged for 10
minutes at 1000 rpm (.about.200.times.g) at 4.degree. C. The
cell-free culture supernatant is removed with a sterile
polypropylene pipet and transferred to sterile polypropylene tubes.
Samples are maintained at -30 to -70.degree. C. until analysis. The
samples are analyzed for interferon (.alpha.) by ELISA and for
tumor necrosis factor (.alpha.) by ELISA or IGEN Assay.
[0970] Interferon (.alpha.) and Tumor Necrosis Factor (.alpha.)
Analysis by ELISA:
[0971] Interferon (.alpha.) concentration is determined by ELISA
using a Human Multi-Species kit from PBL Biomedical Laboratories,
New Brunswick, N.J. Results are expressed in pg/mL.
[0972] Tumor necrosis factor (.alpha.) (TNF) concentration is
determined using ELISA kits available from Biosource International,
Camarillo, Calif. Alternately, the TNF concentration can be
determined by ORIGEN M-Series Immunoassay and read on an IGEN M-8
analyzer from IGEN International, Gaithersburg, Md. The immunoassay
uses a human TNF capture and detection antibody pair from Biosource
International, Camarillo, Calif. Results are expressed in
pg/mL.
TNF-.alpha.Inhibition in Mouse Cells
[0973] Certain compounds of the invention may modulate cytokine
biosynthesis by inhibiting production of tumor necrosis factor
.alpha. (TNF-.alpha.) when tested using the method described
below.
[0974] The mouse macrophage cell line Raw 264.7 is used to assess
the ability of compounds to inhibit tumor necrosis factor-.alpha.
(TNF-.alpha.) production upon stimulation by lipopolysaccharide
(LPS).
[0975] Single Concentration Assay:
[0976] Blood Cell Preparation for Culture
[0977] Raw cells (ATCC) are harvested by gentle scraping and then
counted. The cell suspension is brought to 3.times.10.sup.5
cells/mL in RPMI with 10% fetal bovine serum (FBS). Cell suspension
(100 .mu.L) is added to 96-well flat bottom sterile tissues culture
plates (Becton Dickinson Labware, Lincoln Park, N.J.). The final
concentration of cells is 3.times.10.sup.4 cells/well. The plates
are incubated for 3 hours. Prior to the addition of test compound
the medium is replaced with colorless RPMI medium with 3% FBS.
[0978] Compound Preparation
[0979] The compounds are solubilized in dimethyl sulfoxide (DMSO).
The DMSO concentration should not exceed a final concentration of
1% for addition to the culture wells. Compounds are tested at 5
.mu.M. LPS (Lipopolysaccaride from Salmonella typhimurium,
Sigma-Aldrich) is diluted with colorless RPMI to the EC.sub.70
concentration as measured by a dose response assay.
[0980] Incubation
[0981] A solution of test compound (1 .mu.l) is added to each well.
The plates are mixed on a microtiter plate shaker for 1 minute and
then placed in an incubator. Twenty minutes later the solution of
LPS (1 .mu.L, EC.sub.70 concentration .about.10 ng/ml) is added and
the plates are mixed for 1 minute on a shaker. The plates are
incubated for 18 to 24 hours at 37.degree. C. in a 5% carbon
dioxide atmosphere.
[0982] TNF-.alpha. Analysis
[0983] Following the incubation the supernatant is removed with a
pipet. TNF-.alpha. concentration is determined by ELISA using a
mouse TNF-.alpha. kit (from Biosource International, Camarillo,
Calif.). Results are expressed in pg/mL. TNF-.alpha. expression
upon LPS stimulation alone is considered a 100% response.
[0984] Dose Response Assay:
[0985] Blood Cell Preparation for Culture
[0986] Raw cells (ATCC) are harvested by gentle scraping and then
counted. The cell suspension is brought to 4.times.10.sup.5
cells/mL in RPMI with 10% FBS. Cell suspension (250 .mu.L) is added
to 48-well flat bottom sterile tissues culture plates (Costar,
Cambridge, Mass.). The final concentration of cells is
1.times.10.sup.5 cells/well. The plates are incubated for 3 hours.
Prior to the addition of test compound the medium, is replaced with
colorless RPMI medium with 3% FBS.
[0987] Compound Preparation
[0988] The compounds are solubilized in dimethyl sulfoxide (DMSO).
The DMSO concentration should not exceed a final concentration of
1% for addition to the culture wells. Compounds are tested at 0.03,
0.1, 0.3, 1, 3, 5 and 10 .mu.M. LPS (Lipopolysaccaride from
Salmonella typhimurium, Sigma-Aldrich) is diluted with colorless
RPMI to the EC.sub.70 concentration as measured by dose response
assay.
[0989] Incubation
[0990] A solution of test compound (200 .mu.l) is added to each
well. The plates are mixed on a microtiter plate shaker for 1
minute and then placed in an incubator. Twenty minutes later the
solution of LPS (200 .mu.L, EC.sub.70 concentration .about.10
ng/ml) is added and the plates are mixed for 1 minute on a shaker.
The plates are incubated for 18 to 24 hours at 37.degree. C. in a
5% carbon dioxide atmosphere.
[0991] TNF-.alpha. Analysis
[0992] Following the incubation the supernatant is removed with a
pipet. TNF-.alpha. concentration is determined by ELISA using a
mouse TNF-.alpha. kit (from Biosource International, Camarillo,
Calif.). Results are expressed in pg/mL. TNF-.alpha. expression
upon LPS stimulation alone is considered a 100% response.
[0993] The complete disclosures of the patents, patent documents,
and publications cited herein are incorporated by reference in
their entirety as if each were individually incorporated. Various
modifications and alterations to this invention will become
apparent to those skilled in the art without departing from the
scope and spirit of this invention. It should be understood that
this invention is not intended to be unduly limited by the
illustrative embodiments and examples set forth herein and that
such examples and embodiments are presented by way of example only
with the scope of the invention intended to be limited only by the
claims set forth herein as follows.
* * * * *